Pharmaceutical Granulation

Validation of USP Methods - Incorporation of ISO Terms!

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

Validation of USP Methods - Incorporation of ISO Terms!

In the first supplement of the USP 32, the revised, general chapter <1225> - Validation of Compendial Methods - was published. This chapter describes the requisite performance characteristics that should be considered to prove the validation of a method in the case of its submission to the Pharmacopoeia.

It is striking that terms coming from ISO standards have also been incorporated, although the wording in pharmaceutical surroundings was until now oriented towards the ICH Guidelines, especially ICH Q2(R1).

This was also the topic of the publication entitled "Making Sense of Trueness, Precision, Accuracy, and Uncertainty" in the Pharmacopoeial Forum of May-June 2008. This article reviews the differences between the terms when used in ICH and ISO. It also states that the terms "trueness" and "uncertainty" do not even exist in the ICH and the USP. The conclusions drawn in this article are as follows: The terms should be clarified in the USP. These clarifications could easily be added to the General Chapters <1010> und <1225>. In the longer term, the USP encourages continued harmonisation of terminology among the involved parties (ISO, ICH, VIM - International Vocabulary of Metrology) and other interested parties.

In the revised chapter <1225> of the first supplement to USP 32, these terms have now been incorporated from ISO 5725-1 and ISO 3534-1.

And the term "reportable value", established from the OOS discussions in recent years, is now also incorporated in this USP chapter.

The requisite performance characteristics to be considered in validation of the types of methods in order to prove their suitability for the USP (accuracy, precision, specificity, detection limit, quantitation limit, linearity, range and ruggedness) remained unchanged.

And when is it necessary to revalidate? Revalidation may become necessary when a revised analytical method is submitted to the USP or when an established, general method is to be used for a new product or for a new starting material.

Validation Findings in FDA Warning Letters 2008

noreply@blogger.com (J. Aguilar) — Thu, 09 Apr 2009 08:01:00 +0000

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.

Pharmacy History

noreply@blogger.com (J. Aguilar) — Thu, 26 Mar 2009 06:48:00 +0000

The pharmacy history

Pharmacy History 1 1226686818538034 9

View more presentations from Shujah A.r.

Investigation Medicinal Products

noreply@blogger.com (J. Aguilar) — Sun, 22 Mar 2009 08:51:00 +0000

EMEA publishes Questions and Answers on the Quality of IMPs

The European Medicines Agency (EMEA) has published new Q&As on the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials (CHMP/QWP/185401/2004). Final reference is given for each question.

1. Question: Setting specifications for impurities
On which basis should specifications for related impurities be set?

Answer:
Safety considerations should be taken into account. The limits should be supported by the impurity profiles of batches of active substance used in non-clinical and clinical studies. Results between batches should be consistent (or the clinical batches should show better purity results than non-clinical and previous clinical batches).
Compliance with ICH requirements is not required, if proper justification is provided.

2. Question: Substantial amendments (Chapter 8)
How should industry notify amendments?

Answer:
The table in the Guideline on the Requirements to the Chemical and Pharmaceutical Quality Documentation Concerning IMPs in Clinical Trials (CHMP/QWP/185401/2004) gives examples of what should be notified as substantial amendments and of changes where a notification will not be necessary. The list is not exhaustive, and the Sponsor should decide on a case-by-case basis if an amendment is to be classified as substantial or not.
Substantial amendments should be notified using the Notification of Amendment Form. Relevant updated sections of the documentation should be submitted, not the entire Quality Investigational Medicinal Product Dossier (IMPD).
For non-substantial amendments the form should not be used. The relevant authorities should be informed about relevant amendments together with an overall IMPD update or a substantial amendment. Documentation should not be submitted, but the relevant documentation should be recorded within the company.

3. Question: Shelf life extensions
Which information should be included in the file in order to make shelf life extensions without notification of a substantial amendment?

Answer:
The criteria based on which it is intended to extend shelf life during an on-going study should be given. The information should include extension protocol limiting the maximum time period for extrapolation. In the case of any significant negative trend for stability data observed during long-term and accelerated testing, the sponsor should commit to notify any shelf life extension as a substantial amendment.

4. Question: Batch data
Are Certificates of Analysis needed?

Answer:
No, tabulated batch results are sufficient. Data for representative batches should be included in the batch analysis table of the IMPD. Results for batches controlled according to previous, (wider) specifications are acceptable if the results comply with the specification for the planned clinical trial. The results should cover the relevant strengths, but the batches do not need to be the same that will be used in the clinical trial.

Source: EMEA Inspections QWP Questions and Answers

Quantitative Analysis-Instrumental Methods

noreply@blogger.com (J. Aguilar) — Mon, 09 Feb 2009 20:41:00 +0000

In this video you can learn some topic related with Instrumental methods used at the Pharmaceutical Industry

Introduction to Process using PAT

noreply@blogger.com (J. Aguilar) — Mon, 09 Feb 2009 20:39:00 +0000

Introduction to Automation using PAT

Powder Characterization for Formulation and Processing

noreply@blogger.com (J. Aguilar) — Mon, 09 Feb 2009 20:29:00 +0000

The current trend within the pharmaceutical industry toward more efficient development, manufacturing, and specification is fueling demand for analytical tools that provide highly relevant information. Effective powder characterization has a valuable role to play.

Tim Freeman
Pharmaceutical Technology

Freeman Technology

Despite advances in alternative methods, tablets remain the most widely used method of drug delivery. Well-manufactured tablets are extremely stable, provide excellent dose uniformity, and are well accepted by users. Formulation development is, however, challenging, with the apparent simplicity of a tablet belying the challenges of its manufacture.

Tablet production demands the transformation of a relatively free-flowing powder into a compressed solid form. Stability is a defining performance characteristic, but rapid dissolution is also essential for efficient in vivo delivery. Other properties such as taste, smoothness, and shape must also be taken into account. As a result, tablets are complex multicomponent blends of binders, glidants, lubricants, disintegrants, sweeteners, flavors, pigments and, of course, active pharmaceutical ingredients (APIs).

Tableting has a long history, and substantial experience has been gained over many decades. Processors and formulators have traditionally relied heavily on this experience, taking an empirical, as opposed to knowledge-based, approach. Now, with the introduction of quality by design, the situation is changing. There is recognition of the importance of more fundamental knowledge and of investing heavily in its development.

Taking tableting as an example unit operation, this article explores how modern powder characterization techniques can provide valuable information that enhances understanding. Measuring dynamic, bulk, and shear properties of powders allows identification of the parameters that best define product performance, both during processing and in final application. This knowledge underpins fast, successful formulation development and effective process control.

The demands of the tableting process

Direct-compression tableting is a common method of solid dosage form manufacture. With this approach, the constituents of the tablet are blended and are then fed directly to the press. In most cases, however, the formulation cannot be used without first completing several preprocessing steps such as a wet or dry granulation. Granulating the blend reduces problems such as segregation and improves flow behavior by densifying and increasing the size of particles.

Figure 1 shows a schematic of a single-sided rotary tablet press. Powder flows from the hopper or intermediate bulk container, down the transfer chute, and onto the table. The blend is distributed through the feeder and flows gravimetrically into the die. As the table rotates, excess powder is scraped away from the top of the die before the punches apply compression to create the tablet. The tablets are ejected before the dies reach the filling point again.

Because the aim is to produce tablets of defined weight, geometry, hardness, and composition, consistent flow from the hopper onto the table and through the feeder into the die is necessary. A free-flowing powder may avoid blockages and intermittent flow, but it also may be more prone to flooding or segregation (the separation of dissimilar-sized particles).

During the compression stage, the goal is to produce a stable form that can be cleanly ejected from the press with minimal force. Achieving this objective makes other aspects of powder behavior important. For example, if excess air is retained in the die and compressed along with the powder, then it may expand once the compression force is removed, causing the tablet to burst or cap. Blends that release air relatively easily are therefore preferred. Tablet strength also is directly affected by cohesivity—compressive strength. A blend with low cohesivity may form a weak, unstable tablet, while highly cohesive materials may adhere to the tablet press and cause variability in fill weight.

This brief analysis highlights some of the compromises involved in addressing just a few of the issues connected with processing and final product quality. Other performance criteria overlay additional and often conflicting priorities. For example, fines may be attractive to a formulator because they help achieve rapid dissolution and increase tablet-compression strength but are problematic during processing because they increase the risk of cohesive behavior and affect productivity. Balancing these variables is the formulator's art.

Experience-based formulation is possible, and indeed still common, but greater emphasis on effective processing and early definition of the design space is reducing the scope for error. Formulators need tools that provide relevant data at an early stage, thereby allowing rationalization of experience in terms of quantifiable parameters. This result gives insight and understanding, promoting a knowledge-based approach. Processors too require data to understand the reasons for both good and poor performance at the press. Such knowledge feeds back into formulation development and facilitates the successful processing of challenging blends.

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CELLULOSE ESTERS

noreply@blogger.com (J. Aguilar) — Tue, 03 Feb 2009 06:38:00 +0000

In the Lab: CELLULOSE ESTERS

TODD STROTHER, PHD
FT-NIR for Discriminant Analysis of Cellulose

Cellulose esters are heavily used for controlled drug delivery

Cellulose derivatives, widely found in foods and pharmaceuticals, are used as emulsifiers, dispersing agents, and thickeners. While cellulose itself is not readily soluble in water, various derivative esters have increased solubility, even if these esters are hydrophobic in nature. This seemingly contradictory behavior occurs because the ester groups disrupt the cellulose crystalline structure. In addition to solubility, various esters have different glass transition temperatures, tensile strengths, and water vapor transmission rates. The amount and type of esterification present in cellulose material therefore becomes exceedingly important when considering its use in pharmaceuticals or food products.

This article will discuss the discriminant analysis of cellulose esters using Fourier transform near infrared (FT-NIR) spectroscopy. The article will provide an overview of cellulose derivatives, looking at how cellulose acetate esters are heavily exploited in pharmaceuticals, where they are typically used for controlled drug delivery. Current methods will be discussed, along with the issues affecting available technologies. Emerging methods and future developments-and their effects on the pharmaceutical and drug delivery market in general-will also be considered. The purpose of this article is to demonstrate that an FT-NIR analyzer can quickly and accurately identify and classify cellulose esters.

Figure 1. Release Rate in Acidic Conditions

Typical dissolution profile for a drug compounded with various cellulose acetate esters.

ALL IMAGES COURTESY OF THERMO FISHER SCIENTIFIC
Good Excipients and Coatings

Cellulose acetate esters are used a great deal in pharmaceuticals, typically for controlled drug delivery. Their controlled porosity and solubility make them good excipients and coatings for solid dosage forms. Each sugar residue in cellulose has three hydroxyl groups that are amenable to esterification. Quantitative measurement of the amount of ester present is reported either by percent or by degree of substitution (DS). The DS of a particular material, which will fall between zero and three, indicates the average number of ester groups found on each residue.

To provide for greater complexity, cellulose acetate materials are further derivatized with proprionate or butyrate groups to various degrees. As a result, a given cellulose material may primarily be a cellulose acetate with additional proprionate or butyrate ester groups. The sheer variety of available esters allows a great deal of control over how a drug performs after ingestion.

FT-NIR spectroscopy can be used to confirm the identity of cellulose esters with great speed and accuracy; it has proven to be a superior method for identifying and classifying different materials. FT-NIR uses the part of the electromagnetic spectrum between the UV-visible and the mid-infrared regions to detect overtone and combination vibrations present in nearly all organic molecules. The unique structure of specific organic molecules allows them to generate characteristic spectral patterns when irradiated with near-infrared light.

As a spectroscopic technique, FT-NIR can generate results in seconds without sample preparation or destruction, a clear advantage over other spectroscopic methods. Because FT-NIR spectroscopy can discriminate among similar raw materials, a Thermo Scientific Antaris FT-NIR analyzer was chosen to analyze different cellulose acetate esters for this study.

A Range of Materials

Identity and characteristics of cellulose materials used in the experiments.
Nine cellulosic materials were obtained from Eastman Chemical Company (Kings-port, Tenn.) or Acros Organics (Fair Lawn, N.J.). The materials represented a range of type and degree of esterification. While microcrystalline cellulose had no ester groups present, the others were acetate esters with various amounts of additional proprionyl or butyryl moieties (see Table 1, above).

Three samples of each material were taken and placed in glass vials. The samples were analyzed three or four times using the integrating sphere module, for a total of ten scans for each material. Between scans, the contents in the vials were shaken and then compacted by gently rapping the vial on a solid surface. This method ensured consistency in the density of the material while simultaneously effecting variety in sampled material. The samples were scanned between 10,000 and 4,000 cm-1 at a resolution of 8 cm-1 with 16 scans per analysis. No attenuator screen was in place, and a 1X gain was used. Baseline offsets were minimized by analyzing the data as first-derivative spectra. The data demonstrated the variation among the different cellulose materials in the first derivative spectra as well as the regions used in the chemometric analysis.

Discriminant analysis was performed using Thermo Scientific TQ Analyst software. The multiplicative signal correction option was chosen for the path length, and Norris smoothing (segment length = 5; gap = 5) was performed. Additionally, unique distributions were calculated for each class using a technique commonly referred to as SIMCA (soft independent modeling of class analogy). A principal component scores plot shows exceptionally clear discrimination among the various cellulose ester types. The cellulose acetate butyrate esters are widely separated from each other and the other cellulose derivatives; the cellulose acetate proprionate esters require a different region to discriminate. The data show that the spectral differences among these materials range from 5,050 to 4,800 cm-1. A second chemometric analysis on this region using similar parameters allowed discrimination between these proprionate esters (see Figure 2a and 2b, p. 48).

Validating Analysis

To validate the effectiveness of this analysis, new samples of the cellulose materials were obtained and scanned. These materials were then classified according to the chemometric analysis described above (see Table 2, p. 47). All of the test samples were correctly identified and placed into their proper classes. The data indicate that the method is suitable for identifying new samples of the cellulose materials.

Cellulose acetate esters are used a great deal in pharmaceuticals, typically for controlled drug delivery. Their controlled porosity and solubility make them good excipients and coatings for solid dosage forms.

Validation samples were analyzed using the parameters determined from the calibration materials. All of the validation samples were correctly identified.

Figure 2a. Spectral differences among sample materials

Spectral variation was between 5,050 and 4,800 cm-1 for the cellulose acetate proportionate esters.

Figure 2b. A chemometric analysis of sample materials

A principal component scores plot indicating good discrimination between the cellulose acetate proportionate esters.
As the study shows, a series of cellulose materials, including various cellulose acetate esters, were obtained and analyzed using an FT-NIR analyzer. Chemometric analysis showed there were sufficient spectral differences among the different materials, even when the chemical differences were subtle. These spectral differences were used to build a chemo-metric model and correctly identify new samples. This study demonstrates the validity of using FT-NIR for proper classification of various cellulose and cellulose ester materials. ?

Strother is an application scientist at Thermo Fisher Scientific; for more information, e-mail analyze@thermofisher.com.

The New APIC Quick Guide for Procuring GMP-Compliant APIs

noreply@blogger.com (J. Aguilar) — Sat, 31 Jan 2009 18:22:00 +0000

The New APIC Quick Guide for Procuring GMP-Compliant APIs
As a reaction to the growing number of substandard or counterfeit active pharmaceutical ingredients (APIs) that are increasingly introduced into the supply chains, the APIC - the interest group of the European API manufacturers - created a document intended as a guideline for assessing sources of APIs. This "APIC Quick Guide for API Sourcing" bears the subtitle "APIs from legitimate and reliable sources" and is directed both at medicinal product companies and at API manufacturers. In five subject-related chapters, the document gives practical advice on the question with the help of which measures the medicinal products manufacturer as the ultimate buyer of APIs can assess the supplier's quality. Conversely, the guide also contains numerous practical recommendations for the API manufacturer, which he can implement in order to demonstrate that he manufactures his APIs in compliance with ICH Q7 or EC GMP Guide Part 2.
The following subjects are dealt with in the individual chapters:
Supply Chain: Agents, Brokers, Distributors, Repackers, Relabelers
Audits
Supporting Documentation
Packaging: labeling, tamper-proof sealing
Material Inspection, Sampling, Analysis, Impurity Profile
The chapters "Audits" and "Supporting Documentation" are dealt with in great detail and include quite practice-oriented tips, e. g. the recommendation to auditors to change the agenda at short notice and to re-inspect areas that have already been looked at in order to uncover scenarios that may have been created artificially. As another important point to get an overall picture of the audited site, the text mentions the Product Quality Review which gives the auditor a good overview of the GMP-compliant manufacture of an API.
What is important according to the APIC Quick Guide, is good and intense communication structures between the medicinal product manufacturer and the API supplier. There is an explicit reference to the topic of packaging, labelling and tamper-resistant closures. The API manufacturer should supply his customers with samples of the used labels and closures so that counterfeits can be spotted unmistakeably and quickly.
With its up-to-date and practical recommendations, the "APIC Quick Guide" represents an ideal complement to APIC's recently revised "How-to-do" document, which interprets the ICH Q7 guideline. However, the introductory chapter of the guide points out that these recommendations should be understood as elements of a jigsaw puzzle within the framework of a comprehensive supplier qualification, i. e. a risk-based reflection does have to be undertaken in advance in order to determine the reasonableness of the individual measures - depending on the API supplier in question. The Procurement of GMP-compliant APIs is also the topic of a conference with major stakeholders from industry and authority in Brussels, Belgium, on 13 - 14 March 2009.
The "APIC Quick Guide" can be found here.
Author:Dr Gerhard Becker

High-Potency APIs: Containment and Handling Issues

noreply@blogger.com (J. Aguilar) — Thu, 29 Jan 2009 22:20:00 +0000

High-Potency APIs: Containment and Handling Issues
The author explains the planning, equipment, and facility design requried for manufacturing HPAPIs and specialized requirements for handling these compounds.
Sep 1, 2008By: David BormettPharmaceutical Technology

SAFCA significant proportion of new drugs under development contain high-potency active pharmaceutical ingredients (HPAPIs), which is leading to explosive growth in demand for their production. The cytotoxicity of HPAPIs, however, presents handling challenges and requires heavy investment in specialized containment to ensure that employees and their environment are protected from exposure. This article examines the planning, equipment, and facility design of chemical and biologic HPAPIs as well as biologic–HPAPI conjugate manufacture. It also outlines the efforts made by the pharmaceutical industry to develop voluntary standards for HPAPI production and handling.
During the last decade, the demand for HPAPIs has grown rapidly, mainly as a result of advances in clinical pharmacology and oncology research. There is particular interest in HPAPI–antibody conjugate technology, which uses monoclonal antibodies to selectively deliver HPAPIs to specific cancer tumors. When conjugated to the antibody, the HPAPI targets cancer cells specifically and thereby spares nontarget cells many of the toxic effects. Wyeth's "Mylotarg" (gemtuzumab ozogamicin) is an example of such a drug. It is commercialized for treating acute myeloid leukemia, and numerous other antibody drug conjugates are in preclinical or clinical trials.
Compared with the overall growth in the pharmaceutical market of about 7% per year, HPAPIs are estimated to have an annual growth of 12% (1, 2). They account for about 12% of the total pharmaceutical market, and this share is set to rise strongly (3). Although this emerging market is attractive, it presents a significant challenge for pharmaceutical manufacturers to upgrade existing facilities that are set up to handle only nonpotent APIs—the challenge being the major cost associated with the specialized containment needed to ensure that employees and their environment are protected from exposure. Many contract manufacturers are also building new facilities that are designed specifically for the manufacture of HPAPIs, which require an investment of millions of dollars beyond typical GMP (good manufacturing practices) production facilities. This investment may include specialized facilities for HPAPI–antibody conjugations that incorporate both potent-compound handling and biologics processing capabilities.
Definition of HPAPIs
The definition of an HPAPI varies depending on the literature; however, APIs deemed to be potent may fall into the following categories (4):1. A pharmacologically active ingredient or intermediate with biological activity at approximately 150 μg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg) 2. An active pharmaceutical ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 μg/m3 of air as an 8-h time-weighted average3. A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses4. Or, by default, a novel compound of unknown potency and toxicity.
Figure 1 (FIGURE 1 IS COURTESY OF SAFC.)The potency of pharmaceutical chemicals is often characterized by OELs in μg/m3; the lower the value, the more potent the chemical and the greater the level of containment that is required. Currently, there is a significant increase in the number of APIs going through development and clinical trials, and into the production environment with OELs well below 10 μg/m3. These processes require specialized containment to ensure that employees and their environment are protected from exposure. Figure 1 shows a facility design of a typical kilo-laboratory (using glassware) for HPAPI handling. The main features are as follows:
Room pressure differentials designed for containment (with monitoring and verification), with the main HPAPI-handling area at negative pressure to surrounding rooms
Airlocks and vestibules around manufacturing and laboratory spaces to provide gowning and degowning areas and proper pressure differentials
Restricted access to ensure that only the necessary trained employees enter the HPAPI-handling areas
HVAC (heating, ventilation, and air conditioning) systems designed for single-pass air—no return, with temperature, humidity, and particulate controls
Misting showers as part of degown and exit vestibules to rinse personal protective equipment (PPE) and gowning prior to removal
Filtration and capture of contaminants, with safe-change filters, both point source (within the isolator, ventilated enclosure) and the general HVAC exhaust system
Preventive maintenance and change-control procedures to ensure that equipment and systems continue to operate properly and according to design specifications.

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Disolucion Presentado en congreso Farmaceutico SEFIG

noreply@blogger.com (J. Aguilar) — Sat, 17 Jan 2009 21:36:00 +0000

Automatizacion del test de disolucion

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1 day ago

Automatizacion del test de disolucion

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estrategia para la automatizacion sin impacto regulatorio

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Science and Technology of Bioadhesive-Based Targeted Oral Delivery Systems

noreply@blogger.com (J. Aguilar) — Sat, 17 Jan 2009 20:06:00 +0000

Science and Technology of Bioadhesive-Based Targeted Oral Delivery Systems
Novel hydrophobic bioadhesive polymers and dosage designs are now available to effectively achieve tailored release kinetics of a broad range of drugs to meet the clinical needs.
Nov 2, 2008By: Avinash Nangia, PhDPharmaceutical TechnologyVolume 32, Issue 11, pp. 100-121

AUTHORThe use of bioadhesive polymers as a means of delivering therapeutic agents to the gastrointestinal tract (GIT) has been a focus of attention during the past two decades (1, 2). Bioadhesive oral drug delivery systems exploit the interaction between the mucus and bioadhesive polymers and thus offer significant advantages (3, 4) (see sidebar). Oral delivery systems formulated with bioadhesive polymers may increase GIT residence time, thereby improving oral bioavailability as the formulation achieves greater opportunity to interact closely with the absorption site (5, 6). Bioadhesive polymeric systems may also be useful for coating damaged esophageal and intestinal wall tissues, thus providing defense against various irritants (7). The ability to maintain an oral delivery system at the target location for an extended period of time has great appeal for the treatment of both local conditions and sustained systemic absorption (8–10).
Despite significant research on bioadhesive polymers, the phenomenon of bioadhesion is not yet fully understood. Adhesion of bioadhesive polymers to mucus is a complex interaction and is regulated to a great extent by the intrinsic properties of the polymer, the biological substrate, and the surrounding environment (11). The term bioadhesion is defined as adhesion to a biological surface (i.e., mucus and/or mucosal surface). Instances in which the polymeric system interacts with the mucus coating only are referred to as mucoadhesion (12). To develop an ideal oral bioadhesive system, one must have a thorough understanding of mucosa, bioadhesive polymers, and mucous-polymer interactions in the physiological environment.
Major attributes of oral bioadhesive based systems (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.)GI mucosa is composed of high molecular weight glycoproteins that are hydrated with a continuous adherent blanket of mucin. Mucin glycoproteins are rich with fucose and sialic acid groups at the terminal ends that provide a net negative charge in the acidic environment. The thickness of the mucin gel layer varies in various regions of the GIT, with thickness ranging between 50 and 500 μm in the stomach to 15–150 μm in the colon. The thickness of the mucus gel that covers the GI epithelium is attributed to the steady state between the mucus secretions and its erosion via enzymatic and mechanical degradation. Cohesion of the mucin gel depends on the glycoprotein concentration.
The mucus layer is created biologically to protect the underlying tissues from diffusing or corrosive elements such as enzymes, acids, and other toxic molecules. As a viscoelastic gel, it helps in the transport of food over the epithelium, thereby minimizing potential erosive damage. The mucus layer, in addition to providing protection, imparts a barrier to drug absorption. The following mucin–polymer interactions have been proposed:
Wetting and swelling of the polymer to permit intimate contact with the biological tissue
Interpenetration of bioadhesive polymer chains and entanglement of polymer and mucin chains
Formation of weak chemical bonds
Sufficient mobility to allow spreading
Water transport followed by mucosal dehydration.
Figure 1: Schematic representation of interactions between bioadhesive and mucus polymer chains. (ALL FIGURES AND TABLES ARE COURTESY OF THE AUTHOR.)As the bioadhesive delivery system comes into contact with the mucus layer, various nonspecific (van der Waals, hydrogen bonding, and hydrophobic interactions) or specific interactions occur between the complimentary structures (see Figure 1). However, these interactions are of limited duration because of the turnover process of mucin. Although this phenomenon is favorable from the toxicological perspective of keeping unwanted materials from gaining access to the body, it is not optimal for maintaining the bioadhesive delivery system at the mucosal surface. Hence, for a bioadhesive delivery system to be successful, it should release drug contents during the limited adhesion time

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Formulation of Sustained-Release Ketorolac Tromethamine Pellets

noreply@blogger.com (J. Aguilar) — Sat, 17 Jan 2009 19:59:00 +0000

Formulation of Sustained-Release Ketorolac Tromethamine Pellets
The authors evaluated the effect of polymer composition on the drug-release profile and the effect of storage conditions on dissolution characteristics.
Dec 2, 2008By: Mohamed Etman, Hala Nada, Aly Nada, Fatma Ismail, Mamdouh Moustafa, Said KhalilPharmaceutical TechnologyVolume 32, Issue 12, pp. 58-61

Ketorolac tromethamine (KT), (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (in 1:1 ratio), is a potent nonsteroidal anti-inflammatory drug (NSAID) without an opioid effect. It is a pyrrolizine carboxylic acid derivative, chemically related to indomethacin and tolmetin (1).
KT is indicated for the short-term management of moderately severe acute pain that would otherwise require treatment with an opioid analgesic. Like other NSAIDs, KT inhibits the activity of the enzyme cyclo-oxygenase, leading to decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid associated with gastrointestinal side effects (1). Oral KT is indicated only for the continuation of therapy following initial parenteral administration. Because of its short half-life (4–6 h), KT must be dosed frequently to maintain its therapeutic effect (2). Therefore it may be advantageous to administer sustained-release formulations to reduce side effects and improve patient compliance.
Previous studies on the risk of gastrointestinal bleeding associated with NSAIDs in animals (3) and in humans (4) proved that bermoprofen and flurbiprofen, respectively, formulated as sustained-release products were effective and well tolerated with fewer gastrointestinal side effects.
The aim of controlled drug therapy is improved efficiency in treatment—that is, achieving the desired effect and maintaining it for an extended period of time. Objectives of sustained-release formulations include minimizing or eliminating patient compliance problems, minimizing drug accumulation in body tissues with chronic dosing, eliminating either local and systemic side effects, reducing or eliminating drug in blood?level fluctuactions (thereby allowing better disease state management), and improving the bioavailability of some drugs. A potential advantage is that the average cost of treatment over an extended time period may be lower than that of a conventional form (5).
Many investigators have studied the effect of using various techniques to prolong KT release. Genc and Hegazy reported on the preparation of sustained-release wax matrix formulations of KT with Compritol (6). The authors investigated the effect of cellulose matrices on controlling the release of KT and reported that by mixing the drug with an optimum amount of nonionic hydroxy propylmethylcellulose (HPMC) or methylcellulose and anionic sodium carboxymethyl cellulose polymers, excellent release profiles close to zero order were obtained (7). Vatsaraj et al. prepared KT swelling-controlled matrix tablets using three cellulose derivatives (8). Rokhade et al. reported on the preparation of controlled-release KT microspheres using gelatin and carboxymethyl cellulose sodium (9).
Eudragit (Rohm Pharma, Darmstadt, Germany) copolymers have been used to prolong KT release in a matrix formulation (10). Eudragit RL and Eudragit RS are insoluble in water and digestive juices. They are capable of swelling, and because of their permeability, the active ingredients are released by diffusion. They are pH-independent, which means that drug release takes place independently of individual variation. Eudragit polymers also have been used by other researchers to prolong the release of diclofenac and ketoprofen (11–13).
The aim of this study was to prepare sustained-release pellets of KT, that would be given twice per day and that would maintain the effective therapeutic concentration for as long as 12 h. The method would involve a simple microencapsulation technique using Eudragit RL and Eudragit RS and nonpareil seeds as carrier.

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Understand Raw Material Quality

noreply@blogger.com (J. Aguilar) — Sat, 17 Jan 2009 19:53:00 +0000

First Things First: Understand Raw Material Quality
By Paul Entrop, Product Team Director, Analyzers, Thermo Electron Corp.
PharmaManufacturing.com
Understanding the impact of raw material variability is critical to ensuring final product quality and to successfully initiating a PAT program.The last few years, and the knowledge that the industry spends over $90 billion each year on manufacturing alone, have brought increased regulatory attention to the importance of controlling the pharmaceutical manufacturing process. FDA's PAT Initiative and the resulting “Guidance to Industry” promises to play a key role in pushing pharmaceutical manufacturing into the 21st century.To start off any PAT program on the right track, and to gain the process understanding required, pharmaceutical manufacturers must start at the very beginning. They must understand the impact that varying raw material quality has on the final product.Existing techniques only address part of the raw material quality picture. Traditional approaches to determining raw material quality are based on identity, chemical purity and pharmacopeial methodologies. These methods are all useful and important, but in most pharmaceutical processes, they are not enough because they can’t address physical changes in the product. Such changes are extremely important in an operation such as tablet manufacturing, in which powdered materials are handled, mixed, modified and compressed, changing their physical attributes.It’s not unusual for OOS tablet batch failures to be traced back to a problem with a raw material ingredient’s physical property. This occurs, even when that raw material passed all the traditional inspection processes in place for incoming materials.NIR’s Role in Quality AssuranceAlready well established as an analytical tool for pharmaceutical testing, FT-NIR can provide information on both chemical quality attributes and physical properties quickly, easily and without destroying the sample.The technique can be used to create a raw material information database containing information on both chemical and physical properties, and batch-to-batch variance. Use of the technique can also speed up quality testing, eliminating the time spent waiting for results, and reducing inventory and the need for raw material quarantine.When part of a properly designed PAT effort, the analytical method offers fast, repeatable and reliable results. Once an NIR raw material database has been set up, links between quality performance later in the process, and FT-NIR spectra can often be established.From these links, causal relationships can be explored and investigated, or the system can be deployed to screen incoming raw materials to determine how suitable they are for the given process. Thus, raw material qualification via FT-NIR can become the first critical control point in the process, enabling the use of more advanced process control techniques.Important points to consider are first and foremost, whether the material is the correct one. Does it meet specifications for purity or water content? Is it useable in the process, given its chemical and physical properties? Often, the same API in a form with a different shape or particle size, can lead to surprising product failures.FT-NIR can help manufacturers address all these issues, allowing users to predict physical characteristics by analyzing spectra and the reference method for the trait. It also allows manufacturability to be predicted based on trait and output data.

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Isn’t It Time to Update cGMPs?

noreply@blogger.com (J. Aguilar) — Sat, 17 Jan 2009 19:50:00 +0000

Isn’t It Time to Update cGMPs?PharmaManufacturing.comFDA 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 RogersIN 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

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

noreply@blogger.com (J. Aguilar) — Sat, 17 Jan 2009 19:14:00 +0000

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.

New ICH Q4B Annexes

noreply@blogger.com (J. Aguilar) — Thu, 15 Jan 2009 20:14:00 +0000

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> Disintegrationcan 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.

Calcium Phosphate Nanoparticles Deliver Chemo Agents

noreply@blogger.com (J. Aguilar) — Wed, 14 Jan 2009 21:40:00 +0000

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

noreply@blogger.com (J. Aguilar) — Tue, 13 Jan 2009 22:41:00 +0000

Introduction to Tablets technology

Tablet and tablet press

View SlideShare presentation or Upload your own. (tags: aguilar johnny)

FDA`s New Process Validation Guidance - A detailed analysis

noreply@blogger.com (J. Aguilar) — Tue, 13 Jan 2009 18:29:00 +0000

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

noreply@blogger.com (J. Aguilar) — Tue, 13 Jan 2009 18:28:00 +0000

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.

Nanoparticle Delivery Vehicle Penetrates Mucus Layer

noreply@blogger.com (J. Aguilar) — Mon, 12 Jan 2009 07:08:00 +0000

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

noreply@blogger.com (J. Aguilar) — Mon, 12 Jan 2009 06:58:00 +0000

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.

Orodispersible tablets: An overview

noreply@blogger.com (J. Aguilar) — Sat, 10 Jan 2009 16:24:00 +0000

Suresh Bandari, Rajendar Kumar Mittapalli, Ramesh Gannu, Yamsani Madhusudan Rao Center for Biopharmaceutics and Pharmacokinetics, University College of Pharmaceutical Sciences, Kakatiya University, Warangal - 506 009, AP, India

Oral drug delivery remains the preferred route for administration of various drugs. Recent developments in the technology have prompted scientists to develop orally disintegrating tablets (ODTs) with improved patient compliance and convenience. ODTs are solid unit dosage forms, which disintegrate or dissolve rapidly in the mouth without chewing and water. Orally disintegrating tablets provide an advantage particularly for pediatric and geriatric populations who have difficulty in swallowing conventional tablets and capsules. This review describes the various formulation aspects, disintegrants employed and technologies developed for ODTs, along with various excipients, evaluation tests, marketed formulations, and drugs explored in this field.

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Nanoparticle: Drug delivery system for cancer therapy

noreply@blogger.com (J. Aguilar) — Sat, 10 Jan 2009 16:18:00 +0000

Nanoparticle: Drug delivery system for cancer therapyNisha Mary Joseph1, Pramod Kumar Sharma21 School of Pharmacy, College of Health Sciences, Mekelle University, Mekelle, Ethiopia2 Institute of Bundelkhand University, Jhansi, Uttar Pradesh, India

Nanoparticle has emerged as a promising strategy for the efficient delivery of drugs used in the treatment of cancer by avoiding the reticuloendothelial system, utilizing the enhanced permeability and retention effect and tumor-specific targeting. Delivery methods using nanoparticle are highlighted including both degradable and non-degradable polymers. The preparation techniques include emulsion polymerization, micelle polymerization, desolvation of macromolecule, and emulsion-solvent evaporation methods. The particle size of the polymeric nanoparticle is in the nanometer range (10-1000 nm) and is dependent on the method of preparation employed.

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