Pharmaceutical Technology (Johnny Aguilar)

WHO Publishes Guidelines on the Use of Quality Risk Management

2010-09-27T05:19:00.000-07:00

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

2010-09-24T00:10:00.000-07:00

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

2010-06-16T05:14:00.000-07:00

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

2009-04-16T15:04:00.001-07:00

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

2009-04-09T01:03:00.001-07:00

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!

2009-04-09T01:02:00.000-07:00

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

2009-04-09T01:00:00.000-07:00

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

2009-03-30T22:08:00.001-07:00

Preformulation Guide

View more documents from Vijayendrakumar.

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

2009-03-29T01:38:00.000-07:00

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

2009-03-25T23:34:00.001-07:00

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

2009-03-22T01:52:00.001-07:00

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

2009-03-22T01:50:00.000-07:00

European Recommendations on Dissolution Testing

2009-03-22T01:48:00.001-07:00

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?

2009-03-11T13:15:00.000-07:00

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

2009-03-07T03:12:00.001-08:00

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

2009-03-07T03:08:00.001-08:00

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

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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

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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

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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

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Introduction to the analythical technique of Mass Spectrometry

Validation

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Introduction to the amaizing world of Validation

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

New Dimensions in Tablet Imaging

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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

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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?

2009-01-31T10:23:00.000-08:00

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

2009-01-29T14:15:00.000-08:00

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

FDA Collaborates on Nanotechnology Research

2009-01-17T12:04:00.001-08:00

FDA Collaborates on Nanotechnology Research

The US Food and Drug Administration seeks to understand nanotechnology better and exercise appropriate oversight over products that incorporate it.

Nov 2, 2008
By: Jill Wechsler
Pharmaceutical Technology
Volume 32, Issue 11

Nanotechnology has many potential applications in the pharmaceutical industry, and is already being used in consumer products such as sunscreen. But some questions about nanotechnology's interaction with the body and effects on the environment remain unanswered. The US Food and Drug Administration seeks to understand nanotechnology better and exercise appropriate oversight over products that incorporate it.

To address scientific and regulatory issues raised by nanotechnological products, FDA is conducting research in several areas. One lead project will study the dermal penetration and characterization of nanoparticles in sunscreens. Many nanotechnology research projects involve FDA collaboration with other federal agencies, academia, international organizations, and industry. FDA cochairs the nanotechnology subcommittee of the Interagency Oncology Task Force with the National Cancer Institute (NCI) at the National Institutes of Health (NIH). A collaboration with the NIH NanoHealth Enterprise aims to share data relating to nanotechnology product development, including research about failed product candidates and biological interactions of certain nanoscale materials.

An important research partner for FDA is the National Institute of Standards and Technology (NIST), which is engaged in several projects involving the selection of standard reference nanomaterials. FDA, NCI, and NIST jointly support the Nanotechnology Characterization Laboratory (NCL), which works with academia and industry to translate "nano" into the clinical realm. NCL is characterizing nanoparticles, conducting structure activity relationship studies and facilitating regulatory review of nanotechnology constructs. A new project is to evaluate the size, purity, and composition of new imaging agents from General Electric to determine toxicology. FDA also cochairs the federal government's Nanotechnology Environmental Health Implications working group and is active in the Nanotechnology Policy Coordination Group, which looks at policy issues across all government agencies.

International harmonization and coordination is of growing importance as nanotechnology develops globally. FDA helps track international interactions in this area as a member of the federal government's Global Issues in Nanotechnology task force. The agency is actively involved in testing 14 nanomaterials for 59 endpoints with members of the Organization of Economic Cooperation and Development. Discussions related to nanotechnology are taking place under the International Cooperation on Cosmetic Regulation, the World Health Organization, and the United Nations's Food and Agriculture Organization. For medical devices, FDA officials discuss these issues through the Global Harmonization Task Force. And bilateral discussions are taking place with major trading partners to review risk-assessment methods, data needs, and reporting standards.

For more on this topic, see "Nanotechnology Challenges FDA and Manufacturers".

Revalidation” on its last legs

2009-01-17T11:56:00.000-08:00

Revalidation” on its last legs
I participated in an ISPE webinar yesterday with FDA’s Grace McNally regarding the agency’s recently released draft guidance, Process Validation: General Principles and Practices. The guidance is meant to serve as a revision to the 1987 Guideline on General Principles of Process Validation.
Applicable to both large- and small-molecule drugs as well as APIs (but not medical devices), the new draft guidance takes FDA’s quality-by-design and life-cycle approaches by the horns and aims to steer industry even farther down this new track of pharmaceutical manufacturing.
The draft guidance, expected to be finalized by the end of 2009, says McNally, breaks down process validation into three stages: process design, process qualification, and continued process verification. This third area focuses on what industry has often referred to as “revalidation,” but FDA is trying to get out of that mindset and no longer use that term. Gone are the days where three batches of qualified product meant it was time to go to market. Rather, “reproducibility” and “periodic evaluation” are critical, said McNally. “The three batches aren’t important…it’s what you’re looking for in those batches that’s important,” she said.
The overall message behind the draft guidance, she explained, is that companies need to have enough data—and the right data—to feel confident about their product and to be able to justify to FDA and patients why their process and end product will be safe and effective time and time again. FDA’s goal is for manufacturers to better link process development to their commercial process so that a true life-cycle approach is carried out (QbD, PAT, and the ICH quality guidelines really come into play here).
Some webinar participants questioned whether the draft guidance applies to legacy products. “There’s no need to go back to five-year-old DOE records or open new studies and processes,” said McNally. But most companies who are concerned about quality are reviewing their products and processes at least once a year and when companies go through this activity, they may want to keep the draft guidance’s third stage in mind, she said.
Other concerns arose from participants regarding potential conflicts with other existing guidelines such as ICH Q7A and the aseptic processing guidance. McNally said that the new draft guidance is not meant to conflict with any current standards, but that any foreseen problems should be submitted to the agency as part of the review-and-comment process.
Of note, said McNally, the comment period is being extended by 30 days from Jan. 20 to Feb. 20, 2009 to allow industry more time to provide feedback. Comments can be submitted electronically at www.regulations.gov.

Isn’t It Time to Update cGMPs?

2009-01-17T11:46:00.001-08:00

Isn’t It Time to Update cGMPs?
PharmaManufacturing.com
FDA needs to improve its public communications and to connect older written guidances, such as cGMPs, to its new initiatives.
By Agnes Shanley, Editor in Chief
“Even if you’re on the right track, you’ll get run over if you just sit there.”
– Will Rogers
IN JUNE, the U.S. Food and Drug Administration (FDA) celebrated its hundredth anniversary quietly, with commemorative programs and a retrospective on its Web site. In the post-Vioxx, FDA-bashing era, the Agency wasn’t about to get carried away.
Unfortunately, not too many people cared all that much. Then, in the midst of all the staid festivities, came a blast from Rep. Henry Waxman whose office released a scathing report charging that FDA enforcement activity has weakened considerably during the Bush Administration (see "Waxman Thrusts, FDA Parries, No One Wins").

click here to see all the article

Drying Requires Functional Model

2009-01-17T11:36:00.001-08:00

Drying Requires Functional ModelBy Emil W. CiurczakPharmaManufacturing.comA brief look at how PAT methods are being applied to better understand and characterize the pharmaceutical drying process.At Interphex 2008 in Philadelphia, David Radspinner, chairman of the ASTM E-5503 subcommittee on general pharmaceutical standards and marketing manager with Thermo Fisher Scientific, shared his views on Process Analytical Technologies (PAT) and Quality by Design (QbD).In order for the industry to realize the full benefits of QbD and PAT, he said, it must change the way that it views its processes, even processes that seem as well established as drying. The key is moving from a “parametric” to a “functional” process description, which requires a different strategy on the regulatory, scientific and quality management sides. This article will review cases that show how PAT, and methods including mass spectroscopy (MS), Near Infrared (NIR) spectroscopy, and differential scanning calorimetry (DSC), are being used to change the way that drug manufacturers describe the drying process and how they are using that information to better control and optimize that process. This is not meant to be an exhaustive or detailed analysis, but rather a summary.

To see all the article click here

Drying Requires Functional Model

2009-01-17T11:34:00.000-08:00

Drying Requires Functional Model
By Emil W. Ciurczak
PharmaManufacturing.com
A brief look at how PAT methods are being applied to better understand and characterize the pharmaceutical drying process.
At Interphex 2008 in Philadelphia, David Radspinner, chairman of the ASTM E-5503 subcommittee on general pharmaceutical standards and marketing manager with Thermo Fisher Scientific, shared his views on Process Analytical Technologies (PAT) and Quality by Design (QbD).
In order for the industry to realize the full benefits of QbD and PAT, he said, it must change the way that it views its processes, even processes that seem as well established as drying. The key is moving from a “parametric” to a “functional” process description, which requires a different strategy on the regulatory, scientific and quality management sides.
This article will review cases that show how PAT, and methods including mass spectroscopy (MS), Near Infrared (NIR) spectroscopy, and differential scanning calorimetry (DSC), are being used to change the way that drug manufacturers describe the drying process and how they are using that information to better control and optimize that process. This is not meant to be an exhaustive or detailed analysis, but rather a summary.

To see all the article click here

The Fitness for Purpose of Analytical Methods: A Laboratory Guide to Method Validation and Related Topics

2009-01-17T11:23:00.000-08:00

The Fitness for Purpose of Analytical Methods: A Laboratory Guide to Method Validation and Related Topics
Contents: This guide, produced by a correspondence group, comprising mainly Eurachem members is based on an earlier LGC-produced draft. A number of papers have been published promoting validation at a policy level. Others give guidance on validation for particular applications and the use of interlaboratory trials. The Eurachem guide aims to fill the gap in between by providing guidance on the various elements of validation (when methods should be validated, who carries out the validation, how methods should be validated, use of blanks, standards and replication) and is directed primarily towards laboratories working in isolation. Related issues are also dealt with: use of validated methods; designing quality control from valid-ation data; implications of validation data for reporting; and documentation of methods. The guide contains an extensive bibliography including sector specific guidance and annexes list officially recognised definitions and a protocol for method documentation. After successfully collaborating to produce guidance notes for chemical laboratories seeking accreditation to EN 45001, Eurachem and EA identified microbiology as being another area requiring similar attention.
Availability: English language versions (edition 1.0 1998) are available from VAM. Alternatively, you may download the guide from this website (pdf, 236 kB). Translations: the guide has been translated into Czech, Japanese, Lithuanian, Polish and Spanish. For details please contact the Eurachem representative in the respective country or the Eurachem Secretariat.

Uncertainties in qualitative testing and analysis

2009-01-17T11:22:00.001-08:00

Uncertainties in qualitative testing and analysis
Contents: This document has been developed by the Eurachem Measurement Uncertainty Working Group with a view to developing policy and promoting work on the topic. Uncertainties associated with quantitative measurement results have been the subject of considerable activity since the publication of the ISO Guide on the topic. By comparison, the issue of uncertainties in qualitative testing and analysis (referred to elsewhere as “identification certainty”) has received less attention. With the publication of ISO 17025 : 1999, however, interest in uncertainties in testing operations has increased. The problems of establishing uncertainty associated with qualitative tests, such as ‘pass/fail’, identity and comparative identity tests have accordingly become more important. This paper sets out some of the main issues arising for analysts in testing laboratories and accreditation bodies interested in the assessment of uncertainty in qualitative testing. While it does not provide detailed statistical methods for the characterisation of uncertainties in qualitative testing, it does provide general guidance on the main issues.
This document has been published in the Springer journal "Accreditation and Quality Assurance", Accred Qual Assur 5 (2000) 8, 346-348. It is available from the journal's website.The journal's website: http://link.springer.de/link/service/journals/00769/index.htm (click to open this website in a new browser window)
Document location: http://link.springer.de/link/service/journals/00769/papers/0005008/00050346.pdf (47 kB) (click to open this document in a new browser window).

Quality Assurance for Research and Development and Non-routine Analysis

2009-01-17T11:19:00.000-08:00

Quality Assurance for Research and Development and Non-routine Analysis
Contents: This guide, produced by a joint Eurachem/CITAC working party representing industrial, academic, and governmental interests, promotes and describes the concepts of quality assurance in the non-routine environment. The guide promotes a nested approach to quality assurance, dealing with it at a general organisational level, a technical level and a project specific level. It is intended to promote the use of QA as an effective tool for establishing and maintaining quality in R&D and non-routine operations. It does not seek to set criteria for accreditation of R&D although there is a section describing various methods for third party assessment of quality systems. The guidance may form the basis on which accreditation criteria can be set in the future. The guidance is intended to complement the existing CITAC guide (CG1) which describes QA in the routine environment. It is primarily directed towards analytical chemistry establishments but is, in principle, applicable to other sectors. An extensive bibliography is included.
Availability: English language versions (edition 1.0 1998) are available from VAM. Alternatively, you may download the guide from this website (pdf, 203 kB). Translations: A German language version can be downloaded from the Eurachem/D website.

Process Analytical Technology in Product Development and its Impact on Pre-approval Inspections

2009-01-17T11:11:00.000-08:00

Process Analytical Technology in Product Development and its Impact on Pre-approval Inspections
NIR/PAT
Walter Dziki, Ph.D. Abbott Laboratories

The release of the Food and Drug Administration's (FDA) guidances on process analytical technology (PAT) - A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance [Ref 1] and the Pharmaceutical cGMPs for the 21st Century - A Risk Based Approach [Ref 2] in September 2004 have ushered in a whole new approach to pre-approval inspections (PAIs) in the pharmaceutical industry. By implementing PAT, pre-defined trials and experiments are no longer necessary to define product quality. Rather, consistent and predictable drug product quality will be demonstrated by using current or new technology, formal experimental design and/ or prior knowledge to gain understanding and scientific knowledge of the active pharmaceutical ingredient (API) and drug product manufacturing. This science driven risk-based approach relies on communicating greater scientific understanding of the API and the drug product to increase the probability of producing a high quality drug product, thus reducing the risk of inconsistent quality. This approach will alleviate concern about producing a product with a significant risk to public health.

EU Commission and EFPIA Activities against Counterfeit Medicine

2009-01-15T12:15:00.001-08:00

EU Commission and EFPIA Activities against Counterfeit Medicine
On 16 December 2008, the European Commission informed in a press release about the "MEDI-FAKE" action, which targeted customs control on illegal medicines entering the EU: On the basis of a risk profile disseminated by the Commission, customs from the 27 Member States put special focus over a two month period on coordinated action to stop illegal medicines from entering the European Union. This first EU coordinated action had tremendous results, with more than 34 million illegal medicines seized. It also highlighted a number of ways of improving the fight against trafficking in illegal, dangerous or counterfeit goods. It paves the way for future similar actions.
The Commission, Member States' customs experts and pharmaceutical specialists met and identified key risk indicators and high risk pharmaceuticals to be the subject of reinforced controls. These were transformed into an agreed common risk profile to target high risk traffic at all points of the external border controls.
The risk profile, together with updated information and results of the controls carried out, was communicated through the Community Risk Management System (CRMS), managed by the Commission. This ensures systematic, real-time exchange of information necessary to achieve equivalent and effective controls at the frontier. The effectiveness of the profile is continuously reinforced by new risk information obtained from immediate feedback.
The effective elements of the profile will continue to be used by Member States in the coming period.
The MEDI-FAKE action has highlighted areas where improvements can be made in the fight against imports of illegal, dangerous or counterfeit goods. It makes it evident that increasing cooperation with industry is very important. The EFCG, a sector group of CEFIC, will organise their 4th Meeting on Strategies for Compliant Pharma Soucring on 13 – 14 May in Brussels. Among other topics the new draft EU Directive to combat counterfeit medicine will be discussed in detail.
EFPIA is working on a project of Coding and Identification of medicinal products. Various coding solutions have been implemented by Member States, each with their own objectives and motivation. The coexistence of these different systems constitutes an obstacle to enhanced tracking and tracing of medicines at an EU level and adds production costs for manufacturing.
This has led EFPIA to recommend the implementation of a standardised identification solution for pharmaceutical products across Europe. This solution is a unique bar code (Data Matrix) supported by a pan-European verification system enabling pharmacists to check each medicine pack before dispensing it to the patient.
This system would contribute to enhancing the safety and security of the supply chain, whilst also addressing the issues of product surveillance and help gain a better understanding of dispensing risks. The new Europe-wide project will solve the problem with the different coding schemes implemented or proposed by different member states.
The EFPIA concept on identification and coding of pharmaceutical products consists in two parts:1. The harmonisation of pharmaceutical products codification throughout Europe via the implementation of a serialised Data Matrix (ECC200) on secondary packaging of all products sold in Europe (product code + batch number + expiry date + serial number)
2. The verification of pharmaceutical products at their point of dispensing (serial numbers)
A presentation is available on the EFPIA web page which informs about the technical details of this project. New coding and identification systems already established or currently under development (e.g. Italy, Turkey) will be discussed at a GMP conference on Tracking and Tracing in Berlin, Germany, on 28 and 29 April.

New ICH Q4B Annexes

2009-01-15T12:12:00.000-08:00

New ICH Q4B Annexes
Under the roof of ICH, the Pharmacopoeial Discussion Group and the ICH Q4B Working Group have been dealing for years with the harmonisation of the requirements laid down in the pharmacopoeias of the three ICH regions. The two groups cooperate intensively.
The Pharmacopoeial Discussion Group was founded in 1990 und comprises representatives from EDQM, MHLW (Japan) and the USP. Its goal is to develop harmonised monographs (for excipients) and for the general chapters of the pharmacopoeia as e.g. for special test procedures. By now the group has progressed quite a bit, and there is a whole series of harmonised chapters and monographs.
The ICH Q4B Expert Working Group (EWG) was established in November 2003 by ICH and originally aimed at evaluating all test methods defined in the ICH Guideline Q6A (Specifications) and whether individual methods are compatible and accepted in the three ICH regions. Results are then published in method specific annexes in various steps, similar to the ICH procedure. The basic proceeding is described in the ICH Guideline Q4B - Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions (step 4 from 1 November 2007).
In this document the term is defined as follows: “Where such status is indicated, any of the official texts from JP, EP, or USP can be substituted one for the other (appropriately referenced) in the ICH regions for purposes of the pharmaceutical registration/approval process.” The complete document is available at http://www.ich.org/LOB/media/MEDIA3092.pdf.
In June 2008 the ICH issued three ICH Q4B Annexes regarding microbiological topics.
In addition the Q4B Annex 5: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Disintegration Test General Chapters (Step 2 from 5 June 2008) was issued. Concluding the Q4B Expert Working Group recommends under the title “Analytic Procedures” that for tablets and capsules the official text of the pharmacopoeias
Ph.Eur. 2.9.1 Disintegration of Tablets and Capsules
JP 6.09 Disintegration Test
USP <701> Disintegration
can be used in the ICH regions interchangeably. In this connection, acceptance criteria were not discussed. It is not clear what constraints possibly result from item 4 (‚Considerations for Implementation’) which, then again, emphasise the perspectives of the individual regions.
This document can be found at http://www.ich.org/LOB/media/MEDIA4723.pdf.

Vibrational Imaging May Improve Drug Monitoring

2009-01-14T13:44:00.001-08:00

Vibrational Imaging May Improve Drug Monitoring
Label-free imaging tracks molecules in living cells

An imaging modality that detects the vibrations in chemical bonds may improve the monitoring of drug delivery in tissue, according to researchers at Harvard University.
In principle, if we can image tissues with Raman contrasts, we can study the efficacy of topically applied medicines.—X. Sunney Xie, PhD, Harvard University

The three-dimensional vibrational imaging technique, called stimulated Raman scattering (SRS), provides specific vibrational signatures of chemical bonds at much greater sensitivity than other imaging methods, the research team reported. The technology works without the need for fluorescent labeling of the molecules being tracked, the researchers said. (Freudiger CW, Min W, Saar BG, et al. Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy. Science. 2009;322(5909):1857-1861.)
“In principle, if we can image tissues with Raman contrasts, we can study the efficacy of topically applied medicines,” said X. Sunney Xie, PhD, a professor of chemistry at Harvard, in an e-mail to PFQ. “In practice, any kind of imaging methods cannot determine efficacy alone; other methods, such as proteomics and genomics, are needed. SRS can do metabolomics very well.” Metabolomics is the study of specific chemical “fingerprints” left behind by cellular processes.
The researchers described use of the technology for a number of biomedical applications, including differentiating between omega-3 fatty acids and other types of fats in living tissue and monitoring the diffusion of topically applied medications through the epidermis.
Dr. Xie said SRS may allow the tracking of drugs in the human body, “as long as the medicine has specific vibrational frequencies. We are developing an endoscope based on coherent Raman scattering contrast, which, I hope, will make this possible.”

Calcium Phosphate Nanoparticles Deliver Chemo Agents

2009-01-14T13:39:00.001-08:00

Calcium Phosphate Nanoparticles Deliver Chemo Agents
Can sneak hydrophobic compounds into cells

Calcium phosphate nanoparticles have the potential to act as cellular stealth bombers, delivering chemotherapeutic drugs or imaging agents to cancerous cells in a hydrophilic, bioresorbable package, researchers say.
We can take highly hydrophobic drugs and make them essentially water-soluble by packaging them within the calcium phosphate nanoparticle.—James H. Adair, PhD, Pennsylvania State University

The particles were shown to deliver the hydrophilic cancer drug ceramide in a number of cell models in a paper published last month in Nano Letters. (Kester M, Heakal Y, Fox T, et al. Calcium phosphate nanocomposite particles for in vitro imaging and encapsulated chemotherapeutic drug delivery to cancer cells. Nano Lett. 2008;8(12):4116-4121.)
“We can take highly hydrophobic drugs and make them essentially water-soluble by packaging them within the calcium phosphate nanoparticle,” said study author James H. Adair, PhD, a professor of materials science and engineering and director of the Particulate Materials Center at Pennsylvania State University.
“We’ve shown that we don’t cause any change in the biochemistry or biophysical chemistry in the cytosol when the calcium phosphate delivers its package,” Dr. Adair said in an interview with PFQ. The particles release their cargo and dissolve into calcium ions and phosphate ions, he said.
Dr. Adair said his colleague Mark Kester, PhD, a professor of pharmacology at Penn State, likened the technology to a stealth bomber. “The cells need calcium and phosphate; the calcium phosphate delivers the chemotherapeutic without the cell actually knowing what is inside the particle, so we deliver the chemotherapeutic very stealthily,” Dr. Adair said.
The next step in the research will be to show that the nanoparticles deliver their load specifically to the tissue of interest, cancerous lesions, Dr. Adair said. “This is something we’re currently working on and will be reporting in the next three or four months,” he said.

Tablet and tablet press

2009-01-13T14:42:00.001-08:00

Introduction to Tablets technology

Tablet and tablet press

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FDA`s New Process Validation Guidance - A detailed analysis

2009-01-13T10:30:00.001-08:00

For quite a while, the new Process Validation Guideline by FDA had been expected, now it has been published as a draft. On a total of 20 pages and subdivided into 7 chapters, the FDA now describes their current thinking with regard to process validation. The chapters are subdivided into:

I Introduction
II Background
III Statutory and Regulatory Requirements for Process Validation
IV Recommendations
V Concurrent Release for Performance Qualification Batches
VI Documentation
VII Analytical Methodology
I Introduction

The introduction points out expressly that process validation is connected to a product life cycle. Thus, process validation includes development towards routine production and routine production itself. Furthermore, the guidance document intends to promote modern manufacturing principles, process improvement, innovations and sound science. It also refers to ICH Q8, 9 and 10 in connection with the life cycle concept.

The introduction then lists the products subject to the guideline: "human drugs", "veterinary drugs", "biological and biotechnology products", "finished products", "combination products" (drug and medical device), but also "Active Pharmaceutical Ingredients" (with reference to ICH Q7a). As a countermove, exclusions are listed as well, e. g. medical devices and dietary supplements. It is also pointed out that the guideline does not give any information on the documentation necessary to apply for a marketing authorisation. The guideline does not apply to the validation of "automated process control systems".

II Background

The history briefly deals with the FDA Guideline on Process Validation of 1987, the basic principles of which have been taken up again in the new draft. Interestingly, the text expressly mentions the GHTF Guideline on Process Validation relevant to medical devices as being likewise useful for drug manufacturing. The current guidance document is based on experience values gathered since 1987 and also on the FDA Initiative cGMPs for the 21st century - a risk-based approach. Here, the text contains another reference to modern manufacturing techniques and to "risk management" and "quality management tools" and "concepts" - however, without going into detail.

What is new is the definition of process validation as "the collection and evaluation of data, from the process design stage through production, which establishes scientific evidence that a process is capable of consistently delivering quality products". Thus, process validation is now split up into 3 stages:

Stage 1 "Process Design" (The commercial process is based on experiences gained from development and scale-up)
Stage 2 "Process Qualification" (During this stage, the reproducible, commercial scale is confirmed on the basis of process design)
Stage 3 "Continued Process Verification" (This stage is meant to show that the process is in a state of control during routine production)
The text states expressly that in practice these 3 stages might overlap. With emphasis, it urges manufacturers to prove with a high degree of assurance that the product can be manufactured according to the quality attributes before a batch is placed on the market. For this purpose, data from laboratory-, scale-up and industrial scale are meant to be used. The data are explicitly meant to cover conditions involving a great risk of process variation.

For this reason, the manufacturer should

understand the process variations
detect these process variations and assess their extent
understand the influence on the process and the product
and control such variations depending on the risk they represent
Again, the text points out expressly that qualification activities lacking the basis of a sound process understanding will not lead to an accordingly qualitatively safe product. The chapter closes by pointing out that the process must be maintained during routine operation. This includes materials, equipment, the environment, personnel and changes in the manufacturing procedures.

III Statutory and Regulatory Requirements for Process Validation

In this chapter, the FDA refers to paragraphs in 21 Code of Federal Regulation 210/211 that also have to be applied with regard to validation (and qualification of equipment): 211.100(a), 211.110(a)(b), 211.160(b)(3), 211.165 (a)(c)(d), 211.180(e), 211.42, 211.63, 211,68.

IV Recommendations

This is the central chapter of the guidance. At the beginning, Good Project Management and good archiving are pointed out as effective and efficient means for the product life cycle. A team approach to process validation is mentioned as well, with a statistician listed as possible team member. Furthermore, the text reminds of the fact that the full support of senior management is necessary. All studies conducted within the framework of process validation should be documented accordingly and conducted on the basis of sound scientific principles.
Then the recommended activities in the 3 stages are dealt with emphatically.

Stage 1 - Process Design

a) Building and Capturing Process Knowledge and Understanding: In this stage 1, the manufacturing process is meant to be defined, which will then be reflected in the manufacturing and testing documentation. Also in view of Q10, it is expressly pointed out that earlier development stages do not have to be conducted under cGMP. However, here, too, the basis should be sound scientific methods and principles, including Good Documentation Practice. It is considered to be no regulatory expectation that the process be developed and tested until it fails, but the combination of conditions involving a high process risk should be known. In order to achieve this level of process understanding, among other things the implementation of design of experiments in connection with risk analysis tools is recommended. However, other methods, like classical laboratory tests, are also considered as acceptable. What is considered to be essential is the adequate documentation of the process understanding based on rationales, above all in view of the life cycle.

b) Establishing a Strategy for Process Control : Process knowledge and understanding are considered to be the basis for process control. Apart from in-process controls, the text mentions the possible use of Process Analytical Technologies (PAT) and quotes the corresponding PAT guideline.

Stage 2 - Process Qualification

It is meant to prove that the process design is suitable for reproducibly manufacturing commercial batches. This stage has 2 elements: On the one hand the qualification activities regarding premises and equipment, on the other hand performance qualification (PQ). Strictly speaking, this stage encompasses those activities that are currently summarised under process validation: On the basis of qualified equipment, it is then demonstrated that the process can create a product in conformity with the specifications.

The text deals with the constituents of the qualification activities that are the prerequisites for PQ. Without mentioning the terms DQ, IQ, OQ, these activities are described as constituents of the qualification. The necessary documentation on qualification, too, is dealt with. The description of qualification activities are possible as individual plans or as part of a project plan. The possibility to integrate risk management in order to determine priorities and scope of performance and documentation is only mentioned as a "can" option. The contents of the plan should be:

1. Description of the tests
2. Acceptance criteria
3. a schedule
4. responsibilities
5. Information on the documentation and release of the qualification results
6. Data on the change control procedure

The results are meant to be summarised in a report making reference to the acceptance criteria in the plan. Both the plan and the report are meant to be reviewed and released by the quality control unit.

A specific subchapter is dedicated to the performance qualification approach, the second element of stage 2 in process validation. The PQ combines the qualified premises and equipment as well as the trained personnel with the commercial manufacturing process. What could in principle be regarded as a definition of PQ is the document's statement: "A successful PQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected". The PQ is considered to be an important milestone within the product life cycle. Its completion is a prerequisite for marketing, and the decision for marketing the product should be based on data gained from the commercial manufacturing scale, if necessary supported by laboratory and scale-up studies.

The guidance points out expressly that a sound science should serve as approach to PQ. This goes as far as the FDA requiring in the guidance: "We strongly recommend firms employ objective measures (e.g. , statistical metrics), wherever feasible and meaningful to achieve adequate assurance". Insofar, according to the guidance, the scope of PQ regarding sampling, additional tests is more comprehensive than in normal production. Finally, the text points to very specific aspects of biotechnological manufacture and to PAT implementations within the framework of PQ, which take account of a different PQ approach.

The PQ plan (here called "protocol") is meant to discuss the following points:

1. The manufacturing conditions including the parameters to be set, the process limits and the use of raw material
2. Data that are collected and how they are evaluated
3. Tests to be performed (IPC, release, characterisation) and acceptance criteria for each significant process step
4. A detailed sampling plan (where, how much, how often) based on a statistical basis (within a batch and between batches) equalling a risk analysis
5. Criteria providing a rationale for the question whether the process constantly produces a qualitative product. Among them are a description of the statistical methods used for data analysis (referring to variabilities within a batch, but also between batches) and the description of the handling of deviations
6. If need be, qualification aspects of the premises and equipment, training certificates and a verification of the materials used (raw materials and primary packaging materials)
7. Validation status of analytical methods used for measurements in process, for in-process tests and tests on the finished product
8. Review and release by the corresponding departments and the quality unit

An individual item regulates the performance of the PQ tests and reporting: Not new, but still mentioned in the text is the requirement not to carry out the activities until the protocols have been released. Changes to the protocols should be evaluated correspondingly and released by the departments concerned and by the quality unit. The PQ batches are meant to be performed by production staff under normal conditions. This puts and end to discussions about "worst case" conditions within the framework of the validation runs.

Required components of the PQ report:

1. Discussion of the results with cross references to the PQ protocol
2. A summary and evaluation of the data according to the specifications in the protocol
3. Evaluation of all unexpected observations and additional data compared to the protocol
4. Summary and discussion of all "manufacturing nonconformances", like e.g. deviations
5. Detailed description of corrective actions or changes with regard to procedures and controls that have already been laid down
6. Clear indication of a result if the data show that the process is in compliance with the specifications in the protocol and that the process is in a sufficient state of control
7. All necessary reviews and releases by the departments and the quality unit

Stage 3 - Continued Process Verification

During this stage 3, the objective is to keep up the validated state of the process also in routine production. For this the manufacturer is required to establish a system detecting unplanned process variations. Shifts are meant to be evaluated accordingly so that the process does not get out of control. There is a direct reference to 21 CFR 211.180(e) in order to support this ongoing programme. The data must be statistically trended, and the analysis be done by a trained person. The text recommends explicitly that a statistician or at least an employee trained in statistical techniques works out the sampling plans and carries out the evaluation of the data with regard to process stability and process capability. The evaluation and the trending should be done according to SOPs. These evaluations are meant to be reviewed by the quality unit in order to detect changes in the process (alert limits) at an early stage and to be able to implement process improvements. Also with regard to unexpected process changes that can also occur in a well developed process, the guidance recommends "that the manufacturer use quantitative, statistical methods whenever feasible" in order to identify and characterise them and investigate the root cause. Here, too, variations within a batch and between batches are addressed explicitly. At the beginning of routine production, the guidance recommends the same scope of monitoring activities and samples as in the process qualification stage until enough data have been collected to allow a - statistically secured - adjustment of this scope.

Data from complaints, OOS results, deviations etc. can also give hints regarding process variability. Employees in the production line and in quality assurance should be encouraged to give feedback on the process performance. Operator errors should also be tracked in order to check if training measures are appropriate. The text explicitly recommends regular meetings between quality assurance and production in order to evaluate the above data and to discuss possible trends and drifts with the corresponding correction and follow-up measures.

The above results can then contribute to process improvements. However, the guidance points out that changes may only be implemented in a structured way and with the final approval by the quality assurance. Additional measures regarding process design (stage 1) and process qualification activities (stage 2) might become necessary. Another topic that is rated very important by the guidance is that of maintenance (including calibration). The corresponding maintenance and calibration cycles should then be performed based on the gathered data.

V Concurrent Release of Performance Qualification Batches

In rare cases concurrent release is also possible, i.e. a release of the product before the entire PQ protocol has been completed. Possible cases include orphan drugs (limited demand for the product) and radiopharmaceuticals. Yet, the guidance recommends the manufacturer to contact the FDA before implementing concurrent release. Batches marketed within the framework of concurrent release should be traced back very closely in order to be able to take immediate action in case of complaints (root cause). Furthermore, each batch manufactured under concurrent release should immediately be included in a stability programme.

VI Documentation

Documentation is considered very important during each stage of the process validation life cycle. On the basis of the process design (stage 1), the guidance recommends to draw up process flow charts for the full-scale process. Apart from that, the text refers to 21 CFR 211.22 and 211.100.

VII Analytical Methodology

While analytical methods do not have to be validated in the (early) development stages, but have to be scientifically sound, analytical methods of the clinical phases 2 and 3 are subject to cGMP.

Conclusion: It does not really surprise that the new guidance does not mention a fixed number of validation runs proving process validity. This became already more or less clear in the Compliance Guide on Validation published in 2004. The new guidance relies on a 3-stage life cycle model. The new catchword is "process understanding". New definitions for process validation and performance qualification show the strong connection to "scientific sound". Strong emphasis is also placed on the use of statistical methods. "Modern" methods from the world of six sigma, like DoE, process capability indexes (Cpk) and statistical process control are mentioned directly or indirectly. What does surprise is the non-mention of the qualification stages DQ, IQ, OQ, even though the activities that are usually subsumed under these terms are expressly addressed in the guidance as a basis for PQ. The PQ is now the key element of the process validation life cycle and is meant to be carried out under normal conditions. Thus, worst-case considerations with industrial scale batch sizes are excluded. Within the framework of continued process verification, apart from the topic of trending, maintenance is rated highly. Both revalidation and retrospective validation are not mentioned any longer. It will be interesting to see how industry reacts to this draft. Especially the discontinuation of the "magic 3" - even though long anticipated - will probably (have to?) lead to new rationales in order to prove a validation. The new definition of PQ might lead to irritations. Up till now, PQ was often seen as being primarily related to equipment. It remains to be seen in how far statistics will find their way into process validation.

FDA Pushing Ahead with Quality by Design (QbD) Developments

2009-01-13T10:27:00.001-08:00

With the goal of pushing ahead with the QbD initiative and thus the scientific approach in the context of pharmaceutical process development, the US-American health authority FDA made a contract with the National Institute for Pharmaceutical Technology (NIPTE) for 1,19 million US$. It is intended to have evaluated in the given time frame (until September 2010) how and how far pharmaceutical process- and quality controls and the efficiency of the production can be improved and how further requirements regarding Quality by Design can be derived from the results. These are to be published after completion of the studies and ideally to be used for the creation of new guidance documents.

EMEA Plans Amended Guideline on Parametric Release

2009-01-13T10:25:00.000-08:00

On 26 November 2008, the EMEA published a concept paper on the revision of the Guideline on Parametric Release. The deadline for comments on this paper is February 2009.

The existing Guideline on Parametric Release has dealt in essence with replacing sterility testing in final product testing (release for the market). With the ICH Guidelines Q8, Q9 and Q10, however, the approach has to be much more comprehensive. The principles of Quality by Design, PAT and Real-Time Release have not been taken into account in the guideline. This is meant to be changed. With the extension of the scope of parametric release, not only for sterility testing, but generally all final product tests are intended to be omissible if the requirements laid down in the guideline have been implemented. With the revision of the current guideline, the requirements on the tests of batches imported from third countries into the European Union are also planned to be dealt with, since the advantage of the introduction of the parametric release is more or less inexistent if the test according to the product specifications has to be performed once more after the import into the EU even if parametric release was approved by an EU authority.

The Concept Paper on Parametric Release can be found here.

European Commission Publishes Package of Measures against Counterfeit Medicines

2009-01-13T10:24:00.001-08:00

On 11 December 2008, the European Commission published a press release as well as three legislative proposals intended to improve the supply of safe, innovative and accessible medicinal products in Europe.

The essential message of the press release of 10 December 2008 is the statement by Commission Vice President Günter Verheugen: "We wish to restore the EU's traditional role as the pharmacy of the world." Problems as well as chances arise from the progressing globalisation of the pharmaceutical industry, which has consequences both for the patients and for the competitiveness of the industry. The proposals made by the Commission go beyond combating counterfeit medicines and include three legal proposals as well as further political initiatives, like joint action of the EU member states for a more transparent pricing of medicinal products, support of pharmaceutical research, a closer co-operation with the USA, Japan and Canada with regard to medicines safety as well as an intensified collaboration with Russia, India and China.

The legislative proposals encompass:

Making reliable and easily accessible information on prescription-only medicines available to the public, since currently there are still great differences in this area between the individual EU countries
Extending the EU system for the safety monitoring of medicines ("pharmacovigilance") so that harmonisation will help to avoid a duplication of effort and possible confusion with regard to responsibilities in the individual countries in the future.
Combating counterfeit medicines as well as illegal distribution of medicinal products
An overview of the various papers as well as detailed information can be found on the page of the European Commission.

The dangers to the European population caused by counterfeit or mislabelled medicines are taken very seriously by the Commission and are even compared to the "food-and-feed crisis" of the 1990s. Several scenarios that could become a reality if the Commission remained inactive have been gone through, and the resulting costs to the Community until 2020 have been estimated, with the total sum ranging between 9.5 billion EUR and 116 billion EUR. Against this background, the Commission will tackle among other things the following points intended to lead to an amendment of Directive 2001/83/EC:

Creating a legal basis for the Commission to be able to require specific safety features on the packaging of prescription-only medicinal products
Mandatory site inspections of supplying wholesalers, records of inspected wholesalers in a Community database and harmonised procedures for official inspectors
Stricter requirements on the import of active ingredients, among others the requirement to pharmaceutical manufacturers to inspect all producers of the active ingredients used
As for the safety features on medicinal products, the Commission remains quite vague. They mention the requirements of safety features for certain categories of medicinal products meant to ensure authenticity and traceability. Two examples of possible safety features are given: individual product codes (so-called mass serialisation, where each pack bears its own code that remains unmistakably traceable until it is handed over to the customer at the pharmacy) and product sealing, which would reveal any attempt to open the packaging. The technical requirements on product serialisation as proposed by EFPIA and implemented in Turkey are the subject of the conference ECA Tracking & Tracing.

The Commission back-pedaled on its earlier plan to impose a ban on repackaging (parallel trade). While the ban was still proposed in the discussion paper of March 2008, repackaging is now expressly mentioned as a viable option. The reason for this change is to be found in the imminent threat to about 9000 jobs in parallel trade in the EU as well as in higher costs for the health care system and for social insurance carriers currently benefiting from the cheaper parallel imports.

An item that is expressly excluded from the EU Commission's legislative proposals is the sale of medicinal products via the Internet. It shall remain up to the individual member states to impose bans or give permissions.

The legislative proposals are now being discussed at the European Parliament. They cannot come into force until 18 months after they have been passed by the EU Parliament, which is expected for 2010.

Nanoparticle Delivery Vehicle Penetrates Mucus Layer

2009-01-11T23:10:00.001-08:00

Nanoparticle Delivery Vehicle Penetrates Mucus Layer
Opens doors for local delivery of drugs

Nanoparticles coated with polyethylene glycol (PEG) easily penetrated human mucus in research performed at Johns Hopkins University. Researchers there suggested that drugs protected by a PEG coating could pass through the protective mucus barrier in order to deliver localized therapies more effectively.
We have improved the coatings considerably to allow faster penetration for a wider array of particle sizes.—Samuel K. Lai, PhD, Johns Hopkins University

Synthetic nanoparticles coated with low molecular weight PEG were able to move through undiluted human mucus at sizes of up to 500 microns, according to Samuel K. Lai, PhD, who presented the data at the American Chemical Society meeting in August. (Lai SK, Wang Y-Y, Hanes J. Engineering mucus penetrating particles for transmucosal delivery. Paper presented at: American Chemical Society National Meeting and Exposition; August 20, 2008; Philadelphia.)
“We studied the properties of disease-causing viruses that evolved to infect mucosal surfaces to engineer a coating that enables our drug delivery particles to penetrate mucus layers in minutes. In our new work, we have improved the coatings considerably to allow faster penetration for a wider array of particle sizes,” Dr. Lai said in a news release.
The human mucus barrier was, until recently, thought to be impenetrable to polymer particles as small as 59 nm, according to the abstract of Dr. Lai’s presentation. Because of this perceived barrier, research into long-lasting controlled-release delivery strategies for mucosal sites such as the lungs and the female reproductive tract has lagged, the abstract states.
While the low molecular weight PEG-coated nanoparticles moved easily through mucus, the researchers found that high molecular weight particles moved even more slowly than uncoated nanoparticles. The density of the PEG was “especially critical” with smaller-sized particles, the researchers said.
Drug delivery with this technology could potentially improve localized treatments in areas protected by mucosa, the researchers said. “For example, cervical cancer patients could locally apply chemo drugs inside mucus-penetrating particles, which would then deliver the drug locally in the female reproductive tract at efficient concentrations over prolonged periods of time, instead of delivering it everywhere else in the body,” Dr. Lai said in a news release. “That could drastically reduce the side effects as well as prolong the presence of drugs at the target site.”

Chitosan Nanoparticles Protect Antioxidants

2009-01-11T23:00:00.000-08:00

Chitosan Nanoparticles Protect Antioxidants
Biopolymeric coating could enhance oral delivery

A biopolymeric nanoparticle protected antioxidants from digestive juices, allowing their controlled release over time, according to researchers.
The use of nanoparticles for drug delivery is not new but would be a novel approach for delivering antioxidants to the body.—Ken Ng, PhD, Monash University

The natural polymer chitosan could allow more efficient oral administration of antioxidant catechins, which have poor oral bioavailability, the researchers said.
“The use of nanoparticles for drug delivery is not new but would be a novel approach for delivering antioxidants to the body,” Ken Ng, PhD, a lecturer in pharmaceutical sciences at Monash University in Victoria, Australia, said in an email to PFQ.
Dr. Ng and his colleagues at Monash, Ian Larson, PhD, and graduate student Admire Dube, are preparing their findings for publication in the International Journal of Pharmaceutics.
Dr. Ng said catechins are found in fruits, green tea, wine, and other foods but last only hours in the gastrointestinal environment. These flavonoids are useful not only for their antioxidant properties but also for other biological attributes, including anti-inflammatory, vasodilatory, neuroprotective, and anticancer properties, he said.
“Recently, there has been interest in the use of polymeric nanoparticles as delivery vehicles to improve the oral bioavailability of drugs,” Dr. Ng said. Chitosan, a biopolymer derived from shellfish, is biocompatible and biodegradable, and it adheres to the intestinal mucosal layer, he said.
“We anticipate that encapsulation of catechins in polymeric nanoparticles will address their poor oral bioavailability,” Dr. Ng said.
In their current work, the researchers entrapped (+)-catechin in nanoparticles of chitosan-tripolyphosphate and chitosan-alginate and exposed them in vitro to simulated intestinal fluids. The protected (+)-catechin demonstrated controlled release, according to Dr. Ng.
The next step is to compare the oral bioavailability of catechin-loaded nanoparticles with catechin only in a rat model, Dr. Ng said. “Human trials will have to wait until dosage and toxicological parameters are sorted out in an animal,” he said.

Overal Equipment Effectiveness

2009-01-10T13:11:00.000-08:00

Visual Management an 5S

2009-01-10T13:09:00.000-08:00

Qick Overview of Process Maping

2009-01-10T13:07:00.000-08:00

Introduction to Process Map-Lean

2009-01-10T13:03:00.001-08:00

Pharmaceutical Development with focus on Paediatric Formulations

2009-01-09T16:14:00.001-08:00

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Pharmaceutical Development with focus on Paediatric Formulations

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Handling Highly Active Ingredients

2009-01-09T13:07:00.000-08:00

By Angelo De Palma, Ph.D., Contributing Editor Containment systems which protect workers from highly active or toxic ingredients have come a long way in a relatively short time. Within the past decade, pharmaceutical containment strategies and technologies have changed as radically as the industry itself, says Eliot Cook of Absolute Control Systems (Golden, Colo.). A few short years ago, the industry seemed to be stuck on “barrier isolator” technology—over-engineered boxes that offered containment levels between those of gloveboxes and those of cleanrooms, at costs approaching those of cleanrooms. The term for the equipment was questionable at best, since barriers and isolators do such different things, says consultant Jim Agalloco, president of Agalloco Associates (Belle Meade, N.J.) “When you’re flying in an airplane there’s a barrier between coach and first class, but isolation between the cabin and the outside.” Today’s best containment systems are light years ahead of the old “barrier isolators.” They address the performance drawbacks of fume hoods and biological safety cabinets, and the high installation and operating costs of cleanrooms. Gowning costs at sterile manufacturers can run in the hundreds of thousands of dollars per year when suits and time to frock and defrock are included. “With containment systems, you can work in a lab coat, do everything you need to do with the process, and if you spill material you don’t contaminate the whole facility,” notes Cook. Modern containment strategies are based on containment of unit operations. Disposables have also broken new ground in the form of bags and containers for transferring materials from one operation to the next, and, most interestingly, through flexible-film mini-enclosures that minimize cleaning and related validation. System designs reflect increased a focus on meeting occupational exposure limits (OELs). “Ten years ago, containment system design typically called for an OEL [eight hour occupational exposure limit] of 10 micrograms,” says Patrice ClouÃ© of La CalhÃ¨ne (Rush City, Minn.), which started out over forty years ago, supplying protective equipment for the nuclear industry. “Now, they’re looking at nanograms or picograms.” Manufacturers pay greater attention to containment issues early in the development cycle, says ClouÃ©, before the product and its myriad intermediates and side products have been fully characterized. In bioprocessing, where products in solution rarely pose serious problems to operators, the concern is with living microorganisms. To optimize safe material transfer, La CalhÃ¨ne offers its DPTE platform, designed to permit transfer between environments without compromising enclosure integrity. DPTE systems employ a fixed (alpha) assembly, mounted on the isolator wall, and a mobile (beta) assembly which is attached and sealed to the rigid or flexible container. Using its DPTE BetaBag, ClouÃ© says, allows solids to be transferred directly from one enclosure to another without opening the bag to the work environment or having the outside of the bag enter the containment system.

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Managing Risk in the Manufacture of Oncology Drugs

2009-01-09T13:04:00.001-08:00

Managing Risk in the Manufacture of Oncology Drugs
By Lee Karras, SVP of Operations, AAI Pharma
PharmaManufacturing.com
Containment, lyophilization and cleaning validation all must be top priorities when producing cytotoxic agents.

WHILE THE GLOBAL MARKET for oncology treatments continues to grow at a lightning-fast pace, so do the challenges – specifically, those related to the manufacture of parenteral cytotoxic agents. Worldwide, the market for oncology treatments in 2005 exceeded $37 billion, ranking third behind cardiovascular and CNS at $77 billion and $63 billion, respectively. By 2009, the market for cancer treatments is expected to be $65 billion worldwide (Parexel’s Pharmaceutical R&D Statistical Sourcebook 2006/2007, p. 20; Lehman Brothers Universe, p. 20). This growth will be driven primarily by novel therapeutic biologics such as Avastin, Rituxan and Herceptin.
The market for oncology-related clinical trials has also grown. Oncology represented 17.8%, or the largest share of clinical trial starts in 2005 (Ibid p. 47). With regard to oncology products in development, anticancer compounds rank first worldwide with 2,467 compounds in development as of March 2006 (Parexel’s Pharmaceutical R&D Statistical Sourcebook 2006/2007, p. 49, IMS Life Cycle R&D Focus).
The increased understanding of the molecular basis of cancer pathology has led to cancer treatments becoming more specialized in terms of targeting molecular pathways. However, because these agents are essentially cytostatic in nature (i.e., they limit cell proliferation but do not result in a decrease in tumor mass), they will continue to be used in combination with traditional cytotoxic agents which will decrease tumor mass, ultimately leaving the patient tumor-free and able to live longer and with a better quality of life.
Currently, cytotoxic products represent about $10 billion of the $37 billion oncology market. Eighty percent, or about $8 billion, comes from three parenterally administered drugs — Eloxatin (oxaliplatin), Taxotare (docetaxel) and Gemzar (gemcitabine) — all of which will become generic by 2014. The global market for cytotoxic products is estimated by Datamonitor to peak in 2009 at about $13 billion, but shrink to about $11 billion in 2014 due to generic price erosion (source: Sarah Terry Johnston, Datamonitor).
Manufacturing Cytotoxic Products
In many cases, cytotoxic agents represent compounds whose exposure limits are as low as 0.03 µg/m3 over eight hours. In order to protect production operators and the surrounding environment from exposure, manufacturing operations typically are performed in barrier isolator systems or closed restricted access barrier systems (cRABS). The use of these systems allows for complete containment of the environment where the product is manipulated.
The use of barrier isolator systems allows for complete containment of the environment where the product is manipulated. Within any cRABS or barrier isolator system, the air is HEPA-filtered before being exhausted out of the isolator via a dedicated duct that is directed out of the room. Many advanced isolator systems can both clean and sterilize in place to eliminate the need for disassembly and potential exposure between batches.
In a multi-product facility, disposable tubing/parts are typically used to facilitate quicker batch change-over. However, physical cleaning of the product-contact or product-exposed surfaces is necessary to show absence of the last product before the isolator is opened to the general room environment.
These isolator-based systems allow for not only containment during filling and stoppering but also during formulation/compounding. Further considerations to the flow of personnel, equipment and materials before, during and after manufacturing need to be made in order to ensure proper segregation of “clean” vs. “dirty.” In a normal GMP setting, where traditional parenteral manufacturing occurs, this is critical, but this is even more critical where highly potent, cytotoxic products are manufactured. In addition, this is especially important should the equipment need to be disassembled and taken out of the room for cleaning/sterilization.
Lyophilization
Lyophilization of cytotoxic agents requires additional containment and specialized handling. In the case of manually loaded/unloaded lyophilizers, it is crucial to consider personnel protection from product spill as this could result in the personnel carrying residue into adjacent areas. Separate ingress and egress points with specific degowning areas will, in most cases, ensure residues are not carried into “clean” areas or into the general plant environment. However, manual loading/unloading is becoming less frequent with the advent of more modern and computer-controlled (and robust) loading/unloading systems.

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Ion Spectrometry to Cut Cleaning Validation Time

2009-01-09T12:57:00.000-08:00

Personally my first time when I heart Ion scan technique and the application in cleaning validation I saw an opportunity for the future.

We can avoid HPLC analysis and not wait one day for results I could be obtained in few minutes

Here you can find this interesting article which could help you to understand the technique
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Cleaning validation is a critical part of current Good Manufacturing Practice (cGMP), requiring manufacturers to spell out, and then verify, the procedures that they use to clean their equipment. After cleaning, operators typically use high pressure liquid chromatography (HPLC) to sample reference materials and determine whether cleaning procedures are up to snuff. HPLC may be effective, but it's also time-consuming, and facilities can be down for a day or two, at a cost of $1 million per day, while samples are collected and analyzed.
A new alternative to HPLC, ion mobility spectrometry (IMS), is attracting more attention, and offers the potential to shorten the turnaround time by quickly verifying equipment cleanliness. The market currently is led by Smith's Detection (Warren, N.J.), formed two years ago through the merger of Graseby Dynamics in the U.K., Barringer Instruments and Environmental Technologies Group.
Smith's came out with its first Ionscan spectrometer in the early 1990s. Military and security applications have driven the business. The equipment was widely used during the Gulf War, and has been a mainstay for airport security since the downing of Pan Am Flight 103. However, the company soon realized potential pharmaceutical applications, and established its life sciences division over two years ago---just before September 11, according to division vice president Robert Sandor, a Ph.D. chemist who had previously worked in the lab analytical equipment business.

The company faces competition next year, when GE Infrastructure Sensing (Leicester, U.K.) plans to roll out the first commercial products based on its ITMS (ion trace mobility spectrometry) trace-detection technology, which is now in beta testing. "We will be working closely with pharmaceutical manufacturers and cleaning validation experts to build appropriate libraries of fingerprints and assess overall performance," says marketing director Michael Hardcastle, based in Billerica, Mass.
Smith's claims that its Ionscan-LS, when used with a high-performance injection (HPI) system can reduce downtime by more than 75%. So far, drug manufacturers including Bristol Myers Squibb, Forest Laboratories and Glaxo Smith-Kline, have tested Smith's Ionscan and found that it can shorten cleaning validation time from days to hours, enabling significant reductions in downtime.
Ion spectrometry determines composition and concentrations by how quickly sample ions move through a gas subjected to an electric field---mass, charge, size and shape all help determine each ion's speed. Users say the technique can detect nanogram quantities of compounds, well within the ppm standards required by cGMP. Instead of the preparation and set-up needed for HPLC, which requires highly skilled technicians, Ionscan requires that 1 microliter of solution be placed on a PTFE disk, and then dried for one minute. Ionscan analysis is complete within 45-60 seconds, compared with up to 10 minutes for HPLC.
To detect compounds with high proton affinity such as amines or ketones, the device is typically run in positive mode, using nicotinamide as calibrant and reagent, according to Bristol Myers Squibb scientists, who used the technique to examine five drug formulations, and presented their findings at a recent meeting of the Eastern Analytical Society. For compounds with high electron affinity such as anhydrides, negative mode is used, with methyl salicylate as calibrant and chlorine as reagent.
Bristol Myers Squibb found that using Ionscan reduced the time needed to collect and analyze 20 samples from about five hours to 30 minutes. Forest Laboratories, which is currently implementing Ionscan for its cleaning verification, says it reduced the time needed for each product batch from 1.5 days to 4 hours, Sandor says
In addition Glaxo Smith Kline found that it took technicians a total of 55 minutes to set up and use Ionscan, generate results and have them approved, compared with four hours for HPLC, Sandor says. For each application within the company, Glaxo expects Ionscan to save some $38,480 in labor costs per year, in addition to the savings from reduced downtime. Assuming a cost of $90,000 for the instrument, and leaving downtime out of the equation, the device would pay itself in 2.3 years, according to the company. Smith's technology already has been deployed in analytical labs, and the company expects the systems to move into pilot, and, eventually, full-scale manufacturing operations.
If speed is HPLC's drawback in cleaning validation, ion spectrometry also has its limitations. First, Sandor says, the technology will only work with compounds that are volatilizeable and below about 1200 AMU molecular weight, so it won't work with many biological molecules. However, he says, the technique can be easily applied to 80% of the compounds used in pharmaceutical manufacturing. Both Smith's and GE are pursuing air monitoring applications, and Smith's Sandor foresees applications in raw material identification, content uniformity and dissolution testing.

FDA's PAT Team: Shall We Dance?

2009-01-09T12:54:00.000-08:00

PharmaManufacturing.com
FDA's PAT team aims to take compliance and manufacturing from art to science.TEAM OF THE YEAR AWARD FINALIST, LARGE-SCALE PROJECTS: FDA'S PAT TEAMPAT (Process Analytical Technologies) is the rarest of revolutions. It needed brilliant thinkers and some prodding to get off the ground, but it is now a team-driven movement. If it succeeds, it will mean unprecedented changes for both industry and regulators.Team leader Ajaz Hussain faced many of the same challenges -- silos and tight budgets, for instance, and lack of a quality systems approach -- that corporate manufacturing visionaries face. But, if barriers in industry are calcified, imagine them within a government agency. Getting reviewers, investigators, and compliance officers, and other staff within the Agency's different divisions together was only the first step. Then, they all had to be sold on a radically new vision for compliance.When FDA's original PAT team was assembled in 2002, members were drawn from FDA's review, inspection and compliance sectors. Some had been with the Agency for years, others came from industry. Some knew each other, others didn't.

The team hired a consultant to help break the ice. Team members exchanged stories and got to know each other. They even danced together in one exercise. Reviewers, inspectors and compliance officers all went through the same training. At one batch manufacturing course, they even made product as a team. Lighthearted as they may seem, these activities broke down walls between team members and built the camaraderie that has been a catalyst for the team's success.Of course, the team's real success won't be known for another decade perhaps. But, while still a work in progress, the PAT initiative has undeniably begun a revolution within FDA, and certainly within the pharmaceutical industry, inspiring parallel movements in Europe and Asia. While PAT is just starting to make its way to the shop floor, it has created an unmistakable buzz. Change is afoot. Not a one- or a three-man showTo date, the PAT movement has been associated with a few high-profile champions within FDA -- Ajaz Hussain, but also Ali Afnan and Chris Watts. However, the initiative was truly a team effort involving the FDA steering committee and key personnel throughout the Agency, with input from industry as well. Each member of the PAT team had his or her hands on each and every draft revision of the PAT guidance document, ensuring that the vocabulary and phrasing suited the movement. "The final guidance document reflects a true team approach," says Chris Watts. That team now numbers nearly 30, if you include the PAT review/inspection team, steering committee, policy development team and training coordinators. More members will join the review/inspection team when a second phase of training is completed this year.With the release of the final guidance document last fall, the group now has something to show for its efforts and rally around. Team members from top to bottom now also have the expertise and legitimacy to be effective messengers for the movement, whether spreading the PAT gospel within the Agency through a "train the trainer" approach, or in larger forums such as PAT workshops here and abroad. Using a Six Sigma analogy, Hussain says that each of the team members has essentially reached black belt status, and can now leverage this position to further the cause throughout the Agency and industry.The PAT cadre is now a real team, says Afnan. "Our team is much more than just the sum of its members," he says. "What we're now seeing in our daily activity is uncommon interaction between us. Not a day goes by when we don't talk and communicate with several other members of the team."

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Medical Imaging Monitors Pharmaceutical Process Health

2009-01-09T12:52:00.000-08:00

PharmaManufacturing.com
Tomography is widely used in medical imaging, but also is becoming a useful PAT tool for process development and optimization. In this article, Ken Primrose, principal of Industrial Tomography Systems, discusses electrical resistance tomography (ERT) and its implications for pharmaceutical manufacturing.
By Ken Primrose, Industrial Tomography Systems It’s relatively easy to get on-line data from a point source in a process vessel. But the data are of little value unless your liquor is homogeneous, so that the sensor sees a representative sample of the contents. And how do you know if you have perfect mixing? Scanning the whole volume would be much more valuable, and that’s just what a new technology – electrical process tomography (ERT) – does.

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The Desired State: PAT and the Road to Enlightenment

2009-01-09T12:50:00.000-08:00

By Ajaz S. Hussain, Ph.D., Deputy Director, Office of Pharmaceutical Science, CDER, the U.S. Food and Drug Administration (FDA)
PharmaManufacturing.com
By focusing on the pharmaceutical manufacturing process, ASTM standards for process analytical technology (PAT) promise to bring engineering rigor and proactive decisionmaking to pharmaceutical quality.
Process understanding can be a foundation for innovation and continuous improvement in pharmaceutical development and manufacturing. FDA’s Process Analytical Technology (PAT) initiative, part of the Agency’s 21st Century cGMPs [1-5], reaffirms that message [5-7], but also aims to help the global pharmaceutical community reach a “desired state,” where:
Product quality and performance are achieved and assured by design of effective and efficient manufacturing processes;
Product specifications are based on a mechanistic understanding of how formulation and process factors impact product performance;
Manufacturers are able to effect continuous improvement and continuous "real time" assurance of quality. The phrase “desired state” was first articulated two years ago, at the International Conference on Harmonization (ICH) in Brussels, where the idea of a global, harmonized pharmaceutical quality system began to take shape. The system would be based on science and applicable across a product’s life cycle. First, however, the pharmaceutical community would have to overcome the hurdles—historical, traditional, and cultural—that have prevented it from reaching this nirvana.

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Liquid Mixing

2009-01-09T12:47:00.000-08:00

By Angelo De Palma, Ph.D., Contributing Editor
PharmaManufacturing.com
For consistency and success, there’s no substitute for experience and power.
Page 1 of 3
Liquid mixing and blending would seem to be among the most straightforward of pharmaceutical manufacturing unit operations. Mechanical process mixers have been on the market for more than 100 years, and not much separates mixers for drug making from those used in food and chemical industries. “Sanitary features are the only distinguishing characteristic of pharmaceutical-grade mixers,” says Kevin McNamara of MixMor (Los Angeles). In business for more than half a century, MixMor serves the gamut of process industries but custom-designs most of its pharmaceutical-grade liquid mixer/blenders. Customers pay a premium — between $1,000 and $5,000 — for smooth vessel and impeller designs and all-stainless construction. Many liquid mixing/blending operations are indeed straightforward — those involving two similar liquids, for example. They get complicated with very dissimilar fluids, such as oil and water, or whenever solids are involved. For very thick slurries, manufacturers begin to worry about uniformity, time-to-blend, and the horsepower of mechanical blending units. And for additives that may crystallize or combine with water, one must be on the lookout for the ultimate disaster of a blend: solidifying to rock-hard consistency, right in that brand-new, $100,000 stainless steel reactor.

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Powder Blending From Art to Science

2009-01-09T12:42:00.000-08:00

By Angelo De Palma, Ph.D., Contributing Editor
PharmaManufacturing.com
Predictive models, PAT, and continuous processing promise to reduce variability and improve product quality.
Dry powder blending may be the most widely recognized unit operation in pharmaceutical manufacturing, but it’s also one of the least understood. The uniqueness of each individual drug formulation assures that no two blending processes can ever be identical. Powder blending’s unpredictability has challenged engineers to explain in quantitative terms a phenomenon typically described empirically. One team at Rutgers University (New Brunswick, N.J.), led by engineering professors Benjamin Glasser and Troy Shinbrot, is moving closer to this elusive goal. Their research, so far, has yielded surprising results. For one thing, it suggests that agitating a mixture longer and faster will not always result in a homogeneous blend. Blending that appears uniform may degrade into turbulence, causing ingredients to separate into layers. In one experiment, researchers found that fine glass beads of different sizes blended uniformly at low mixing speeds, but formed distinct layers as mixing speed increased. The researchers were able to identify patterns of granular motion that promoted layer formation and interfered with uniform mixing.

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JIDOKA

2009-01-09T12:38:00.001-08:00

The term jidoka used in the TPS can be defined as "automation with a human touch." The word jidoka traces its roots to the automatic loom invented by Sakichi Toyoda, Founder of the Toyota Group. The automatic loom is a machine that spins thread for cloth and weaves textiles automatically.In the olden days, back-strap looms, ground looms, and high-warp looms were used to manually weave cloth. In 1896, Sakichi Toyoda invented Japan's first self-powered loom called the "Toyoda Power Loom." Subsequently, he incorporated numerous revolutionary inventions into his looms, including the weft-breakage automatic stopping device, which automatically stopped the loom when a thread breakage was detected, the warp supply device, and the automatic shuttle changer. Then, in 1924, Sakichi invented the world's first automatic loom, called the "Type-G Toyoda Automatic Loom (with non-stop shuttle-change motion)" which could change shuttles without stopping operation.The Toyota term "jido" is applied to a machine with a built-in device for making judgments, whereas the regular Japanese term "jido" (automation) is simply applied to a machine that moves on its own. Jidoka refers to "automation with a human touch," as opposed to a machine that simply moves under the monitoring and supervision of an operator.Since the loom stopped when a problem arose, no defective products were produced. This meant that a single operator could be put in charge of numerous looms, resulting in a tremendous improvement in productivity.
The Type-G Toyoda Automatic Loom, the world's first automatic loom with a non-stop shuttle-change motion, was invented by Sakichi Toyoda in 1924. This loom automatically stopped when it detected a problem such as thread breakage.
Since equipment stop when a problem arises, a single operator can visually monitor and efficiently control many machines. As an important tool for this "visual control" or "problem visualization," Toyota plants use a problem display board system called "andon" that allows operators to identify problems in the production line at a glance.
An operator communicating an abnormality
An andon problem display board that communicates abnormalities

Toyota Production System

2009-01-09T12:36:00.000-08:00

"Just-in-Time" means making only "what is needed, when it is needed, and in the amount needed." To efficiently produce a large number of products such as automobiles, which are comprised of some 30,000 parts, it is necessary to create a detailed production plan that includes parts procurement, for example.Supplying "what is needed, when it is needed, and in the amount needed" according to this production plan can eliminate waste, inconsistencies, and unreasonable requirements, resulting in improved productivity.
In the TPS, a unique production control method called the "kanban system" plays an important role. The kanban system has also been called the "Supermarket method" because the idea behind it was borrowed from supermarkets. Supermarkets and mass merchandizing stores use product control cards on which product-related information, such as product name, product code, and storage location, is entered. Because Toyota employed kanban signs in place of the cards for use in production processes, the method came to be called the "kanban system." At Toyota, when a process goes to the preceding process to retrieve parts, it uses a kanban to communicate what parts have been used.- Why use a supermarket concept?A supermarket stocks the items needed by customers when they are needed in the quantity needed, and has all of these items available for sale at any time.Taiichi Ohno (a former Toyota vice president), who promoted the idea of Just-in-Time, applied this concept, equating the supermarket and the customer with the preceding process and the next process, respectively. By having the next process (the customer) go to the preceding process (the supermarket) to retrieve the necessary parts when they are needed and in the amount needed, it was possible to improve upon the existing inefficient production system in which the preceding processes were making excess parts and delivering them to the next process.
Through continuous improvements, the kanban has evolved into the "e-kanban," which is managed using IT and increases productivity even further.
Two kinds of kanban (the production instruction kanban and the parts retrieval kanban) are used for managing parts.

KAIZEN

2009-01-09T12:29:00.000-08:00

Origins and Definition of Kaizen
In the U.S. kaizen is often synonymous with "Kaizen Blitz" or "Kaizen Event." Such events rapidly implement workcells, improve setups or streamline processes. However, a better Japanese word for this activity is kaikaku
In Japanese, the definition of Kaizen is "improvement" and particularly, "Continuous Improvement"-- slow, incremental but constant. Norman Bodek explains this and translates it as "Quick & Easy Kaizen".
Taiichi Ohno and Shigeo Shingo developed both kaizen versions at Toyota. They are important tools for Lean Manufacturing, the Toyota Production System (TPS), Just In Time (JIT) and other effective manufacturing strategies.
Large-Scale Vs. Small-Scale Improvement
Large scale improvement is attractive. It promises quantum jumps in productivity, quality and effectiveness. However, it is difficult to implement because it affects many areas, people and processes. The design must be near-perfect because failure courts disaster. The risks and difficulties work against large-scale improvements.
Small-scale improvements are easier and faster. The risks are low because they generally have limited effect. However, the accumulated effect is often greater than a single large improvement. The Kaizen Blitz is a localized, smaller scale improvement and Mini-Kaizen are very small-scale improvements.

The Kaizen Blitz
The Blitz or Event is a focused, intense, short-term project to improve a process. Substantial resources- Engineering, Maintenance, Cell Operators, and others are available for immediate deployment.
An event usually includes training followed by analysis, design, and re-arrangement of a product line or area. A consultant often orchestrates. The Event normally takes 2-10 days. The results are immediate, dramatic and satisfying.
Mini Kaizen
Before the recent popularity of the Blitz, kaizen meant "Continuous Improvement." This is the slow accumulation of many small developments in processes and quality that, over 50 years, has helped make Toyota the lowest cost and highest quality automobile company in the world. Let's call these improvements "Mini Kaizen."
Mini Kaizen is part of corporate culture. It requires both conscious and sub-conscious thinking about improvements day by day and minute by minute on the part of all employees. It also requires that these same employees possess the skills for this type of thinking.
The mini variation is far more difficult to keep up and takes much longer for results than a blitz. But, as Toyota has demonstrated, it offers a more sustained competitive advantage.

LEAN

2009-01-09T12:28:00.001-08:00

Lean isn't about being skinny (don't I know that).

Lean is not "mean" (although the words rhyme, unfortunately).

Lean does not mean cutting heads in the name of cutting costs (see "Lean is not mean").

"Lean" is the set of management practices based on the Toyota Production System (TPS). The phrase "Lean Production" was coined by a group of MIT researchers who wrote the book "The Machine That Changed The World."

Lean Production is basically the same thing as:

Lean Manufacturing
Lean Enterprise
Lean Thinking
Lean Healthcare
Lean has been applied in manufacturing (factories, product design, and administrative functions) as well as service industries (including healthcare, banking, and government). The U.S. Army has an active "lean" program underway in 2006.

One way of defining lean has two parts:

Eliminate waste and non-value-added activity (NVA)

Have respect for people
The opposite of is value-added, which has a special lean definition. An activity is "value added" if, and only if, these three conditions are met:

The customer must be willing to pay for the activity
The activity must change the "form, fit, or function" of the product, making it closer to the end product that the customer wants and will pay for
The activity must be done right the first time.
"Respect for people" is much harder to define. The stock photo folks in the upper right corner are supposed to represent a lean team. From the way they are dressed, could you tell who the plant manager is? Even with all of the smiles, lean isn't about "being nice" and smiling all of the time. Respect means you hold people accountable to the system, following it and improving it (the notion of "kaizen" or continuous improvement).

Lean leadership is about enabling and empowering people. Lean leadership is about helping people grow professionally and personally, allowing to take pride in their work. Lean leadership recognizes how a system operates (represented by the gears in the upper left). Lean leadership doesn't set targets for people, go back to their office, and then yell at people when they don't hit those targets. Lean leaders spend time coaching people. They spend very little time in their office. They lead people and see what is actually happening rather than managing metrics and reading reports.

Some great lean leaders to read about include Gary Convis, from Toyota, and Tom LaSorda, from Daimler Chrysler. Soak up everything they say about leadership. They "get it." So does Quint Studer, a former hospital CEO whose writings on hospital leadership could have been written by Toyota, eventhough he doesn't call it "lean".

Much of the "people side" of lean was adapted by the teachings of the American professor and consultant W. Edwards Deming, who taught Toyota and other Japanese companies after World War II. Lean was also adapted from Toyota's study of the early practices of Henry Ford and the Ford Motor Company. Note the emphasis on "early." Lean is not strictly a Japanese invention, or is its use limited to Japan or Japanese companies.

Annex to ICH Q8 Pharmaceutical Development reached Step 4

2009-01-08T05:46:00.001-08:00

The International Conference on Harmonisation (ICH) Steering Committee and its expert working groups met in Brussels from November 8 - 13, 2008. Highlights of the meeting achievements are outlined below.
The Annex to ICH Q8 Pharmaceutical Development reached Step 4 in Brussels. This document builds on key concepts outlined in the core guideline, and shows how tools such as Quality by Design could be put into practice. It is envisaged that greater understanding of pharmaceutical and manufacturing sciences will create a basis for more flexible regulatory approaches. The Quality Implementation Working Group that was established at the Portland meeting, will be developing a Q&A document to answer questions arising from the new Q8, Q9, and Q10 guidelines. These quality guidelines promote a more conceptual and flexible approach to pharmaceutical quality."
The parent guideline “Pharmaceutical Development” is now recoded Q8(R1) following the addition of the Annex to the parent guideline and giving more details on elements like:
Quality Target Product Profile
Critical Quality Attributes
Defining a Control Strategy
Risk Assessment
Design Space
and how the related information should be submitted in the CTD format.
Source: ICH Press Release
Compiled by:Wolfgang Schmitt

Industry Changes and Challenges

2009-01-08T03:09:00.000-08:00

To expand coverage amidst the economic crisis, Obama will look for ways to cut healthcare costs.
Dec 2, 2008By: Jill WechslerPharmaceutical TechnologyVolume 32, Issue 12, pp. 30-36

President-elect Barack Obama promised to reshape the nation's healthcare system to provide coverage for millions of uninsured Americans. His strategy is to expand federal and local government programs that provide care for individuals and children and to require employers to "play or pay" to support insurance for workers. During the campaign, Obama stopped short of backing a mandate for universal coverage as advocated by many Democrats, but his proposals still raise the prospect of increased government involvement in the nation's healthcare system.
Expanded coverage fits the main goals of pharmaceutical manufacturers. Third-party payment for healthcare services and products, which shields consumers from the real cost of medicines, has boosted drug use during recent decades. With the establishment of the Medicare Part D drug benefit four years ago, millions of seniors who previously paid for medicines out of pocket gained coverage for a significant portion of drug expenditures. The Part D program has been a boon to the pharmaceutical industry, but it also has put the spotlight on drug costs and value and has justified increased Congressional scrutiny of drug pricing, marketing, safety, and effectiveness.
Although many voters cited healthcare as an important election issue, the need for a new economic stimulus package will take priority over healthcare reform. Under pressure to address rising unemployment and low economic growth, Obama is expected to look for limited changes in the healthcare arena for the time being.

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The Effect of Mill Type on Two Dry-Granulated Placebo Formulations

2009-01-08T02:46:00.000-08:00

The particle-size distribution of a pharmaceutical granulation is an important physical characteristic that influences several aspects of a drug (e.g., mechanical properties, content uniformity, compression characteristics, and dissolution performance). Therefore, it is important to control the particle size of the final granulation to ensure drug-product manufacturability and quality. Various mill types currently are available for the size reduction of dry- and wet-granulated pharmaceutical products. To evaluate these milling technologies and their influence on dry-granulated (roller-compacted) formulations, four different mill types were selected for comparison.
Conventional milling is a mechanical process that passes material through a screen or plate to reduce its size into a uniform particle-size distribution. It has been proposed that mill type directly influences particle-size distribution and, consequently, the quality of the final product. However, other variables also influence the milling process. Engineering design differences such as screen size and thickness, impeller and rotor style, and mill-chamber size and shape all affect material-size reduction. Formulations' physical properties determine how well materials maintain their bonds or shear under stress. Operational variation such as impeller and rotor speed and material feed rate may also influence the final particle size.
The ideal pharmaceutical granulation process should provide short residence time in the mill chamber and pass granules quickly through the mill screen while maintaining the integrity of the granule. The strength of the material being milled has an effect on the final granulation particle-size distribution. Hard granules may increase residence time within the milling chamber and produce an excess of large granules in combination with smaller fine particles, thus creating a bimodal particle-size distribution. Minimizing fines in the final granulation enhances the flow properties of the final granulation and improves weight variation during tableting. An ideal particle-size distribution should minimize the level of granules >840 μm (retained on a 20-mesh sieve) and the level of particles <74 μm (passing through a 200-mesh sieve). Most modern mills have variable-speed drives, and are considered low-energy mills when operated at low speeds (i.e., <1000 rpm). Such mills produce granulation within this desired particle-size range and are commonly used within the pharmaceutical industry for granulation-size reduction.
In this experiment, two immediate-release (IR) dry-granulation placebo formulations were selected to evaluate mill performance. Roller-compaction conditions were established using a roller compactor (Mini-Pactor, Gerteis Maschinen + Processengineering, Jona, Switzerland) to produce ribbon at a target solid fraction of 0.7. Ribbon was manufactured from both formulations and characterized for solid fraction, tensile strength, and thickness. Roller-compaction bypass was measured to establish the fines level within the compacted ribbon before milling. Three well established conventional milling options and one unconventional milling operation were compared head-to-head, and the resulting granulation was evaluated for particle-size distribution, flowability, tabletability, and compactibility.

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FDA Collaborates on Nanotechnology Research

2009-01-08T02:45:00.000-08:00

Nov 2, 2008By: Jill Wechsler Pharmaceutical TechnologyVolume 32, Issue 11

Nanotechnology has many potential applications in the pharmaceutical industry, and is already being used in consumer products such as sunscreen. But some questions about nanotechnology's interaction with the body and effects on the environment remain unanswered. The US Food and Drug Administration seeks to understand nanotechnology better and exercise appropriate oversight over products that incorporate it.
To address scientific and regulatory issues raised by nanotechnological products, FDA is conducting research in several areas. One lead project will study the dermal penetration and characterization of nanoparticles in sunscreens. Many nanotechnology research projects involve FDA collaboration with other federal agencies, academia, international organizations, and industry. FDA cochairs the nanotechnology subcommittee of the Interagency Oncology Task Force with the National Cancer Institute (NCI) at the National Institutes of Health (NIH). A collaboration with the NIH NanoHealth Enterprise aims to share data relating to nanotechnology product development, including research about failed product candidates and biological interactions of certain nanoscale materials.
An important research partner for FDA is the National Institute of Standards and Technology (NIST), which is engaged in several projects involving the selection of standard reference nanomaterials. FDA, NCI, and NIST jointly support the Nanotechnology Characterization Laboratory (NCL), which works with academia and industry to translate "nano" into the clinical realm. NCL is characterizing nanoparticles, conducting structure activity relationship studies and facilitating regulatory review of nanotechnology constructs. A new project is to evaluate the size, purity, and composition of new imaging agents from General Electric to determine toxicology. FDA also cochairs the federal government's Nanotechnology Environmental Health Implications working group and is active in the Nanotechnology Policy Coordination Group, which looks at policy issues across all government agencies.
International harmonization and coordination is of growing importance as nanotechnology develops globally. FDA helps track international interactions in this area as a member of the federal government's Global Issues in Nanotechnology task force. The agency is actively involved in testing 14 nanomaterials for 59 endpoints with members of the Organization of Economic Cooperation and Development. Discussions related to nanotechnology are taking place under the International Cooperation on Cosmetic Regulation, the World Health Organization, and the United Nations's Food and Agriculture Organization. For medical devices, FDA officials discuss these issues through the Global Harmonization Task Force. And bilateral discussions are taking place with major trading partners to review risk-assessment methods, data needs, and reporting standards.

2009-01-08T02:44:00.000-08:00

Life-Cycle Management for Sterile Drugs

2009-01-08T02:30:00.000-08:00

Outsourcing sterile manufacturing involves an integrated approach in product life-cycle management.

Jan 7, 2009
By: Patricia Van Arnum
PTSM: Pharmaceutical Technology Sourcing and Management

Biopharmaceuticals are an increasingly important part of the pharmaceutical industry’s pipeline. Biopharmaceuticals account for roughly 10% of the global pharmaceutical market, and 25% of the pipeline, according to industry estimates. As biotech-based products become more prevalent, managing the life cycles of these products is a critical consideration. Strategies in reformulation, common in solid-dosage product forms, also play and will continue to be part of the life-cycle management of parenteral drugs.

Injection systems are a common delivery method for a parenteral drug, where syringes, vials, or cartridges may be used. “Increasingly complex substances are making more and more demands on the composition of injection systems,” says Herman Piana, key account manager with Vetter Pharma-Fertigung GmbH (Ravensburg, Germany). “Regulatory authorities keep making safety laws more stringent, and drug manufacturers and users are calling for more patient-friendly application systems.”

Prefilled syringes, cartridges, or vials illustrate that trend. The market for prefilled syringes is projected to exceed 1 billion units and achieve annual revenue growth of more than 10% (1). The container-closure system used in prefilled syringes offers several benefits such as simplified drug delivery, greater accuracy in filling, and lower incidience of misidentification, improper dosing, and contamination (1). Given these benefits, prefilled systems can be used in extending product life cycles. A parenteral drug, for example, may be initially packaged in a traditional vial system and later the product form can be changed to a prefilled syringe.

The initial selection or change in the delivery system of a parenteral drug is critical. “Biopharmaceutically manufactured drugs are extremely sensitive to their environment,” says Piana. “All materials that are used such as the type of glass, the various components such as the stoppers and other parts, and the degree of siliconization must be optimally matched with the respective active substance to ensure effectiveness.”

Examples of potential interactions that could lead to unacceptable changes in product quality include:

• Loss of drug-product potency owing to absorption and/or adsorption of the active drug substance or formulation excipient by the syringe

• Accelerated or modified degradation of the drug substance or formulation excipient induced by a chemical leached from the syringe

• Precipitation

• Change in drug-product properties (e.g., pH, biological activity)

• Discoloration of either the dosage form or packaging system

Viewing the product life cycleThe extension of the life cycle of drug through a change in delivery system is one side of the spectrum in drug development. Supporting early-stage development through the supply of clinical trial material supply is the other side. Serving all aspects of the value chain is an important consideration in the business model of contract manufacturers. “The ability to service the entire value chain is particularly important for small biotechnology companies,” says Piana. “A smaller biotech company, for example, may have less experience with commercial manufacture or regulatory filings at that stage as they are working on early-stage drug candidates.” Although the initial relationship of the biopharmaceutical company and a contract manufacturer may focus on the supply of clinical trial materials, that relationship may be expanded to include commercial manufacture depending on the progress of drug development. In developing a business model, contract sterile manufacturers, must consider how they plan to service the various aspects of the value chain. As an example, Vetter is positioning itself as a service provider throughout the value chain. For early-stage development, Vetter Development Service (VDS) provides services and proprietary expertise in the preclinical phase in process development and in clinical production. Support services include pharmaceutical analysis, regulatory affairs, and the development of primary packaging supplies. As an another example, for lyophilized drug substances, dual-chamber syringes may be an option for originators that traditionally market their product in a lyo-vial. A switch to a dual-chamber solution before patent expiry may offer an opportunity to differentiate the product from biosimilars. Vetter is positioned in this area through its “LycoJect” dual-chamber syringe. For commercial manufacturing, the company recently completed several expansions. Vetter added a new 19,000-m2 facility for visual inspection and secondary packaging close to Ravensburg Vetter South, its existing facility, at an investment of approximately EUR 20 million ($29 million). Secondary packaging involves the final packaging of the application system in blister packages and cardboard boxes. The new facility is designed to meet homecare applications, including dual-chamber syringes and cartridges for pen- and autoinjectors and to meet new international requirements, such as the adoption of safety systems for anticounterfeiting. The construction of the new production facilities was completed in August 2008. In September, the first of seven packaging lines started operating. The other six lines will start producing step by step by the spring of 2009. The expansion is in addition to a $100-million investment for a new 16,000-m2 facility near Vetter's headquarters in Ravensburg, Germany, which began full production in early 2007. The facility increased Vetter's production capacity for prefilled injection systems by roughly 30% to 400 million units per year. The facility has a capacity of approximately 90 million units per year. The new facility supports dosage-form studies in the early phases of product development, material for clinical studies, and full commercial manufacturing. The facility has two filling lines for liquid and lyophilized injectable drugs in dual-chamber syringes, single- and dual-chamber cartridges, and vials. References 1. D. Jenke, “Suitability For Use Considerations for Prefilled Syringes,” Pharm. Technol. 32 (4) Drug Delivery Supplement, s30–s33 (2008).

Geometric Density or Envelope Density

2009-01-08T02:25:00.000-08:00

One of the most common density measurements involves the determination of the geometric space occupied within the envelope of a solid material... including any interior voids, cracks or pores. This is called geometric, envelope or bulk density and only equals true density when there are no internal openings in the material being measured.

The volume of irregularly shaped samples can be determined by dry powder displacement using a free-flowing powder and a measuring cylinder, and preferably an Autotap to reproducibly compact the powder around the piece being measured.

Tap Density

2009-01-08T02:20:00.000-08:00

The bulk density of a powder depends on how closely individual particles pack together. The bulk density is affected not only by the true density of the solids, but by the particle size distribution, particle shape and cohesiveness. It is an important property in packaging and powder handling.

Handling or vibration of powdered material can overcome the cohesive forces and allow particles to move relative to one another and so smaller particles can work their way into the spaces between the larger particles. The total volume occupied by the powder decreases and its density increases. Ultimately no further natural particle packing can be measured without the addition of pressure and maximum particle packing has been achieved!

Under controlled conditions of tap rate, drop height and container size, the condition of maximum packing efficiency is highly reproducible. This tap density measurement is formalized, using graduated measuring cylinders, in the British Pharmacopoeia method for Apparent Volume, ISO 787/11 and ASTM standard test methods B527, D1464 and D4781 for tap density, and others.