Is Quality an Idea ?

From an old post in Plaxo;

Ideas never die. Ideas live forever. Once the germ of an idea is born..it remains. So is quality also an idea ? Is quality a thought ? or attitude ? or pursuit for excellence ? whatever it is, but why it is what it is. The philosophical debate on quality will continue. It will give many answers which may or may not fit best to the question that what quality is!

I remember entering the room of a Manager of one pharma company which was tidy, neat and well maintained. The placement of pens and pencils in the pen holder, colours, sketch pens, books, charts and chair - in fact everything was wonderful. Or did I only think that was wonderful ? My attitude or his attitude ?

Alfred Nobel, so distress from his invention of dynamite, raised his wealth for an award - Nobel prize. He thought rather unusual - a quality thought? Does thoughts also have quality ?

But had he never had so much of wealth to offer, what Alfred would have done?? No money - no award. The quality of Life...

You never know - quality is multidimensional, multifaceted, omnipresent and mysteriously hidden in the seed of human thoughts - human thought which have the courage to raise this civilization! Is it?

Is quality an Idea ?

Template for API Quality Agreement

BPTF or Bulk Pharmaceutical Task Force, a SOCMA organization has launched a template for preparing quality agreement to provide guidance for drafting agreements related to the manufacture and release of drug substances regulated by various regulatory agencies. The template is based on the experience of industry members.

For more information and downloading of the template, click here

Schedule L1, GLP on board !

Thanks to Mr Shirgaonkar for this wonderful information !
Knowledge of Good Laboratory Practices is very important in Pharmaceutical industry.
New GLP requirements as per Schedule L1 of Drug Rules will come into effect from 1st November 2010. Topics such as General laboratory requirements,instruments calibration, microbiological testing and internal audit will be covered in this statutory requirement.
It was announced that Ministry of Health has recently notified the Schedule L-1 of Rule 74,78 and 150 E under Drugs and Cosmetics Third Amendment Rule 2008 giving the pharmaceutical industry time till November 1, 2010 for compliance.
The implementation of GLP and the responsibility of companies to comply with them while carrying out quality analysis. GLP stresses on the maintenance of documented quality systems as per the quality manual laid down by the manufacturing unit, and on the technical audit of the quality control laboratory for GLP compliance by an expert/experts appointed by the top management other than the person in charge of the laboratory.
As Mr. Shirgaonkar organises a workshop on GLPs and highlight the incumbent Schedule L1, to know more visit Insight Systems website

Revision of Isopropylbenzene status from Class 3 to Class 2

Keyoor has forwarded an interesting information. The jumping of chemicals from one list to another will continue. The information says that ICH is revising the status of Isopropylbenzene to Class 2 from existing Class 3 ! This is somewhat a demotion of Isopropylbenzene which was previously in the safer Class 3. It also means that there will be an upper specification limit to Isopropylbenzene and which must be continuously monitord and controlled.

Although I could not verify the source of this information, but I am sure Keyoor's information is correct and precise. Please read the following text which is copy-paste version:

Due to new toxicity studies in rats and mice, the solvent Isopropylbenzene is meant to be categorised as Class 2 instead of Class 3. A corresponding ICH draft guideline has been published and released for commenting by the public.

The ICH Guideline Q3C defining the limits for residual solvents as impurities in active pharmaceutical ingredients (APIs) and finished medicinal products as well as the methods for establishing their exposure limits has already been revised four times. The revisions concern among others provisions for calculating the PDEs (PDE = permissible daily exposure, denoting the maximum amount of a solvent that may be taken in with a medicinal product) for the solvents N-Methylpyrrolidone and Tetrahydrofuran. Now the guideline is about to be revised once more, the reason being that new toxicological data have been collected on the solvent Isopropylbenzene (called "Cumene" in the guideline). Hitherto, this substance has been categorised as Class 3, i.e. as a solvent with low toxicity. In general, these solvents have PDE values of 50 mg per day or more. Recent toxicity studies conducted in rats and mice clearly showed a heightened carcinogenic potential so that it has become necessary to assign Isopropylbenzene to the higher Class 2 and to calculate the PDE accordingly.

On 26 March 2010, the ICH Draft Consensus Guideline "Impurities: Guideline for Residual Solvents - PDE for Cumene" was published (Step 2 in the ICH process) and has since been available for commenting by the public. This guideline now requires the calculation of the PDE for Isopropylbenzene according to the rules for Class 2 solvents. After two further steps in the ICH process, this guideline will be integrated into the core document, which will then bear the name ICH Q3C(R5).

This new regulation might require manufacturers of APIs and medicinal products using Isopropylbenzene to make a considerable effort in changing their registration dossier (e. g. as a consequence of changes to the manufacturing process, the analytical methods etc.).

CDSCO Website in its improved version with inclusion of Industry Guidance Documents

CDSCO website in new avatar. Since my last visit to the website, may be at a gap of a year, I realise, CDSCO has included various multidisciplinary topics. Navigation is made easy and search relatively better.
The best part is the inclusion of "Guidance to Industry" documents in the line of US FDA. The recent addition to this is a draft guidance for fixed dose combination.

There are separate sub-section for Medical devices and Diagnostics. Downloads having full text of Drugs & Cosmetics Law;

While all APIs registered as on date in India are listed, there are separate lists for formulations and vaccines registered for import.

There is also a list of all WHO GMP  certified facilities in India which are 817 in number. This information will be useful for foreign manufacturers which wanted to have contract manufacturing or any other kind of in-licensing business from India.

However, still I feel that there could be a better ways of segregation of different categories under the headings of drug products, drug substances, cosmetics, medical devices etc.

Anyway, to start and improve is still better to wait and watch !

To reach the website, click here

What is AIP ?

AIP is Application Integrity Policy. The policy focuses on the integrity of data and information in applications submitted for Agency (FDA) review and approval.
The AIP described Agency's approach regarding the review of applications that may be affected by wrongful acts that raise significant questions regarding data reliability.
Although the guidance document does not create or confer any rights for or on any person and does not operate to bind FDA or the public, it does represent the Agency's current thinking on consistent implementation of the AIP.
The AIP is invoked when a company’s actions raise significant questions about the integrity of data in drug applications including falsification. Under the AIP, FDA asks the company to cooperate with the agency to resolve the questions of data integrity and reliability. This includes implementing a Corrective Action Operating Plan (CAOP) to provide assurance of the integrity.
To download policy document, click here

Has FDA invoked AIP for any Indian company?
To best of my knowledge, there is no other company from India for which AIP has been invoked, except the Japanese-Indian company - Ranbaxy Laboratories Limited.

Given below is a Case Study on AIP invoked to a company, its consequences and handling of events.
U.S. Food and Drug Administration announced that a facility owned by India-based Ranbaxy Laboratories falsified data and test results in approved and pending drug applications. The facility, Paonta Sahib, was already under an FDA Import Alert since September 2008. To address the falsified data, the FDA has invoked its Application Integrity Policy (AIP) against the Paonta Sahib facility. The AIP is invoked when a company’s actions raise significant questions about the integrity of data in drug applications. Under the AIP, the FDA has asked Ranbaxy to cooperate with the agency to resolve the questions of data integrity and reliability. This would include implementing a Corrective Action Operating Plan (CAOP) to provide assurance of the integrity.

What led FDA to invoke AIP to Ranbaxy?
In the backdrop, when two facilities of Ranbaxy Labs were audited by US FDA Inspectors in the February 2006, the inspections reveal significant deviations from cGMP. Ranbaxy issued three responses (March 20, April 20 and May 25) to these observations. However, the FDAs review of Ranbaxy response didn’t helped much and FDA said in its letter about the still valid concerns.
As these responses and the supporting documentation from Ranbaxy continued to be examined by CDER against the filed applications, it was reveled that apart from significant GMP deviations, the company falsified data and test results in approved and pending drug applications.
The AIP memorandum issued by CDER dated February 25th, 2009 says that CDER has determined that “Ranbaxy submitted untrue statements of material fact in abbreviated and new drug applications filed with the Agency. These findings concern the submission of information, such as from stability test results in support of pending and approved drug applications, from the Ranbaxy Laboratories Limited site located at Paonta Sahib”.

The AIP copy can be downloaded from here
For the benefit of readers it is worth to mention that FDA has stated in its website that

“To date, the FDA has no evidence that these drugs do not meet their quality specifications and has not identified any health risks associated with currently marketed Ranbaxy products.”

EMEA is revising Process Validation guidelines

At the end of February 2010, the European Medicines Agency (EMA) published a draft paper revising their process validation guidelines
Elements from the guidelines ICH Q8 (Pharmaceutical Development), ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality Systems) are to flow in, particularly in the process areas of Analytical Technology (PAT), Quality by Design (QbD) and Real Time Release Testing (RTRT).
It is planned that the final document will be ready in the 4th quarter of 2011.

The concept paper on this guideline can be downloaded here

Eudralex revises Part II of the GMP guide

An amendment is made to Part II of the GMP Guide to incorporate principles of Quality Risk Management in line with the ICH Q9 guideline on Quality Risk Management. Amendments correspond to similar changes made to Part I Chapter 1 of the Guide and published in February 2008. A new section on Quality Risk Management is
introduced as section 2.19. The remaining sections of chapter 2 are renumbered. A minor change is made to section 2.21. No other changes have been made.

Deadline for coming into operation 31 July 2010
 
Authors Note:- Eudralex Part II to GMP guide is an adoption of ICH Q7 and gives comprehansive view of GMPs for APIs. To download, click the title of the post !

Handling of OOT for FDA Inspections !!

Concerns to GMPs are generally linked to the fear of FDA Auditors. As if the systems and procedures of organization are designed for the inspectors rather then for the internal improvements. 

First, there is no separate point of view of FDA from cGMP / system requirements. A self justified system with appropriate scientific rational must be acceptable to anyone, including FDA inspectors. 

The OOT procedure must have : 

(a) OOT identifying mechanism 
(b) OOT addressing mechanism (or action / alert program), and 
(c) Link to CAPA. 

The risk assessment study of process highlights the parameters where OOT must be identified. An appropriate study of available data helps in laying the limits for alert and / or action points (which are nothing but OOT action limits). 

The action plan for OOT (alert / action) is different for different parameters. 

The action plan may be linked to CAPA program so that (i) root cause of OOT is identified and (ii) repetition of OOT is eliminated.

Readers Encourage me !

It's good to see you all here following 'Realm of Quality'. Indeed it gives immense pleasure to see the numbers growing - not just for the sake of numbers, but to see you all who are interested to know more on practical GMPs and basic Industrial Quality Management per se.
Currently working on Environment Monitoring for non-sterile Manufacturing. It is taking bit time, but shall come back soon on the requirements which are not recommended by any International guideline.

Mesuring conductivity of purified water

While there is a conductivity meter already installed at the purified water generation system, the absence of on-line conductivity meter prior to the entry point of return loop (to purified water storage tank ) is somewhat not acceptable.
No matter how technically good the purified water generation system is designed with SS 316 water distribution loop with electro polished pipelines (>20 mm diameter), sanitary joints, adequate slope with no ‘dead legs’, but a NO check to conductivity at return loop may jeopardize the overall water system.
Conductivity increases with increase in ions - CO2, pH or an increase in bio-load which is an indication of deteriorating quality of purified water duirng its journey in the loop. This must be checked at all the levels and re-confirmed by testing conductivity at return loop. Therefore, the position of conductivity meter at return loop is most justified.

Change Room and Air Lock - Design & Layout

What is the difference between a ‘change room’ and an ‘air-lock’? When Michael requested for more clarification on change rooms design vis-à-vis pressure differentials and movement of air, I didn’t thought that our discussion will go in so detail. While a change room is generally required for change of outside attire before entering a clean zone, the applied air-pressure differentials makes it an air-lock keeping outside air out and not allowing contamination to fly inside. Thus an airlock divides two different zones or classes of clean areas.
As Michael impressed on our discussions, I thought to share some of the useful bullet points emerging out of it.
Air lock connects two different environments, usually at different pressures, that enable personnel to transfer from one environment to the other.
An air lock is required when the particles from adjacent area is less clean than the clean-room of concern, therefore, the infiltration of particles can be minimized by controlling the air flow direction so that air flows from the clean room to its adjacent space (less clean). This can be easily accomplished by supplying more air than return air (++ condition), thus slightly pressurizing the room.
Above picture gives the schematic view of change room with requirement of pressure differentials across different zones.
See carefully the blue arrows for direction of air –flow, direction in which doors are opening and ‘+’ sign for pressure differentials.

FDA Website in New Avtaar

FDA website is in a new avtaar. The new design of FDA website is dazzaling, easy in navigation and user friendly. Visitors to the new, improved Food and Drug Administration (FDA) Web site will find critical recall and consumer safety alerts now located right up front where they belong. Based on months of feedback from its core audience -- consumers, doctors, and the health care industry -- the FDA designed the new site to place more of the most important and popular information front and center on the home page. (www.fda.gov) One of the biggest changes is the display on the home page of current FDA news items. Reports of safety alerts and product recalls are included and updated regularly. Another high profile job of the FDA, approval of new drugs and medical devices, has also found a spot on the home page. The new site also features an archive of FDA press releases and other news items dating back to 1992. Also featured on the new FDA Web site:Information on "hot topics" such as cell phones and flu vaccines that will be updated regularly. Automated e-mail lists to which the public can subscribe. One list provides a weekly digest of FDA news (summaries of press releases, talk papers, speeches, testimony, and other new postings on the FDA Website). A "reference room" with links to Federal Register notices and background on laws and regulations enforced by FDA. Links to pages maintained by the various FDA centers responsible for regulating food, drugs, biologics, medical devices and other products. Special information for consumers, patients, women, seniors and other audiences. Information about FDA activities such as Freedom of Information, science at FDA and clinical trials. An improved search engine to provide more meaningful and useful results. The alphabetic index also has been thoroughly updated, and there is now a site map for those who find that feature a useful way to locate information. The site also enables users to report problems with products regulated by FDA and to comment on proposed regulations. The FDA also invites visitors to complete this Online User Survey.
http://usgovinfo.about.com/library/weekly/aa112300a.htm

Re-qualification of LAF - Possible requirements

When one of my frined enquired about re-qualifcation requirements of LAF for any reason, it was easy to reply - Hey buddy, go for velocity, linearity, leak test(DOP Test), no. of air changes , temperature and humidity. That's true, these are all the requirements when a LAF needs to be re-qualified, say after re-installation, major maintenance or replacement of major component (e.g. blower).
But let's take a deeper look. In fact re-qualification of a LAF should not be taken as differnet from initial qualification. In case of equipment used in sterile areas (or other wise too), the re-qualification should follow the initial qualification protocol or practice. The point is new DQ should meet new user requirments. The other critical attributes such as velocity, linearity, leak test(DOP Test), temperature and humidity (If requirement are specified) must be addressed with acceptance criteria clearly laid down. However, what is important in this case is the area qualification where the re-qualified LAF is (re-) installed. For this routine area monitoring for vialbe and non-viable particluates can be performed.

Evolution of GMPs - A Refresher Course !

H B Dandekar refreshes the evolution of GMPs globally and in India in in his article in 'Express Pharma Pulse'. An interesting article to abreast knowledge on GMPs and its journey till today.
The excerpts from the article are given below. However for complete article, click here
The evolution of GMP in pharmaceutical manufacturing may be traced back to the year 1960/61, when entire Europe was shaken by the birth of over 10,000 deformed babies by women who had consumed a tranquiliser drug ‘thalidomide’ during the period of their pregnancy. The problem was further compounded when the progeny of some of the deformed (Thalidomide babies) persons was also born deformed. The obvious reason of this major tragedy was either the absence or negligence of a study of proper effects of the new drug on the next generation.
In India, pharma industry started in around 1900 and was mainly focused on formulations. The Drugs and Cosmetics Acts and Rules were brought into effect in 1945. Till the 1970s, the Indian pharma industry was mostly manufacturing formulations with very few bulk drug/active pharma ingredients. Though, by and large, the quality was genuinely maintained, there was no concept of quality assurance. The terms GMP, documentation, SOPs, BMR validation, qualification, internal audit, training, were unheard of. There used to be only quality control. After 1975, there was a major growth in the industry when many Indian pharma companies entered into bulk drug manufacturing, hence, entering the international market. Naturally, they had to follow the stringent quality requirements of World Health Organization (WHO); thus, there was a gradual introduction of GMP through WHO's international quality requirement.
In 1986, a number of patients in one of Mumbai's leading hospitals died of poisoning due to usage of adulterated glycerol. The toxic adulterant found was diethyl glycol. An enquiry committee under the chairmanship of late Justice Lentin brought the people concerned to the task. During a raid on the premises of a scrap dealer in 1992, many rejected labels and cartons in bulk of pharma formulations of a leading multinational pharma companies were found. On interrogation, the scrap dealer confessed to selling these rejected packing materials to a small manufacturer making spurious drugs.
In 1996, one of the brands of the product Co-trimoxazole of a leading multinational pharma company was found to contain an antidiabetes drug—glibenclamide—as a result of a mix up while manufacturing. This resulted in a sudden and drastic rise in blood sugar level and blood pressure of several patterns and many of the affected people were critical after consuming those tablets in an eye camp. The Managing Director of the company left India for Canada.
These are some of the known and major cases found to be violating fundamental quality practices. There may be many unknown cases as well, but all these incidences must have led to many positive changes in the Drugs and Cosmetics Acts, 1941:
1. Around the year 2000, introduction of revised Schedule M gave in detail the requirements as per GMP for the premises and equipments for manufacturing of pharmaceuticals
2. Schedule T introduced GMP requirement of plant and equipment for ayurvedic and unani pharma products
3. Schedule U stated that particulars required to be shown in manufacturing of pharmaceuticals in their records
4. Schedule V introduced the standards of patents and proprietary medicines, and declared therapeutic and prophylactic dosages for certain drugs/vitamins.
The WHO requirement for registration of products for export was still stricter, where a company had to make and submit site master files giving the details of itself and its quality systems, documentation, validation, self inspection/internal audit etc.
The quality requirement in regulatory authorities of developed nations is still more stringent, as filing drug master files and giving exhaustive details of the product manufactured and intended to be exported is a necessity.
Schedule M of Drugs and Cosmetic Acts 1940 regarding GMP and requirements of premises, plants and equipment for manufacturing of pharmaceutical products is quite exhaustive . It covers many aspects eg general requirements, locations/surrounding, building/premises, water system, warehousing area, production area, ancillary area, quality control area, personnel, health, clothing and sanitation, manufacturing, operations and controls, sanitation of manufacturing premises, raw materials, equipment, documentation and records, labels and other printed material, quality assurance, self inspection and quality audit, quality control system, specifications, master formula record, packaging records, batch packaging record, batch processing record, standard operating procedures and records, reference samples, reprocessing and recoveries, distribution records, validation and process validation, product recalls, complains and adverse reactions, and site master file.
The Indian pharma industry is growing at the rate of 10 percent as against the global growth of seven percent. At the same time, the menace of spurious drugs is also increasing at an alarming rate, not to forget the competition from countries like China. All this makes it very essential to not only introduce, but also inculcate the system of GMP. The initial investment cost will be there, but on successful implementation and follow up of GMP the advantages are many e.g. Increase in productivity, reduction in wastages, increase in yield, high moral of staff/work, better working condition, better image of the company.
While introducing GMP it is advisable to do first cost benefit ration of the investment versus returns, plan the products to be manufactured; understand and correctly implement the FDA GMP guideline, take the guidance and advice from the proper people who are experts in the field, appoint qualified and experienced staff to carry out different activities. Finally, GMP should be taken as an attitude. It is an investment which, if made properly, will yield good results tomorrow.

WHO GMP Certification is no more a reqirement for Domestic Manufacturers !

The Economic Times reports that domestic drug makers may not require GMP certificate from WHO. As popularly known within Pharma fraternity, the COPP (Certificate of Pharmaceutical Products) is issued by DCGI on behalf of WHO after a GMP inspection of a firm which intends to export its products. This could be a way forward by DCGI and CDSCO which intents to bring Indian GMPs or Schedule M at par with other international GMP and Quality regulations.
"For marketing medicines within the country, only schedule M certification under the Drugs and Cosmetics Act (DCA) is required. State regulators have been directed that they no longer need to insist for a WHO-GMP certificate from manufacturers while giving them marketing permissions," the official said. GMP is aimed at diminishing the risks inherent in pharmaceutical production. WHO GMP certificate is given based on certain guidelines laid down by WHO through which the regulator ensures that medicines and other medical
products are consistently produced and controlled to the quality standards required for their best use.
For complete News, click here

What's the Quality Anyway ?

It was a usual discussion on the definition of 'Quality'. In fact for every Quality personnel or for those who steps in the domain of Quality, the definition of quality is the most intrigued one. During the days of my training in the Quality Assurance, the first chapter or rather the first thing I was introduced to was the definition of 'Quality'. 

Masters of Quality have spent their lives in giving the most correct, precise and most acceptable definition of 'Quality'. It, in fact have made our life easier as now we have so many thoughts, ideas or definitions of the word called 'Quality'. From 'high degree of excellence' to 'customers delight' everything which describes the characters tics of product / services, conformance to the requirements and acceptability by the end user are covered under these definitions.

These all definitions certainly covers the business interpretation of the word 'quality'. These definitions addresses quality from  - process, product, customer or the conformance  point of view.

Even the standard definition of TQM (total quality management) focus on the strategies for complete (total) involvement of 'quality' in to the business process. However, the word quality remains as such.

The word Quality in its philosophical approach is still bigger then any of the above definition. Away from the business processes and technical jargon's, in my point of view 'quality' is happiness !!

Any act, product or services which gives immense happiness to a customer is certainly emerges out of quality. While the customers can be  - the one who pays, the one who gets, the one who sees, the one who judges, the one who evaluates or the one of experiences.

Afterall, it is the happiness for which each one of us strieves for !

In between Audits and Compliance.

What lies in between Audits and Compliance ? Is it's all same that lies in between the sky and the earth ? Well, I would say No. 

Audits gives observations or findings which are systemic gaps or differences from the laid down 'Quality' (GMP) Systems. The Compliance of such gaps indicates the intentions of the Management, Staff and other stake holders toward the direction in which Company wants to look forward. Compliance is commitment and requires complete understanding of prevailing and intended systems.

In the absence of commitment or understanding of (prevailing or intended) systems, the purpose of Audit is defeated and Compliance is just a piece of show !