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 !

Moving forward with desires and despair

As we move into the new year I wish all my readers a very Happy and Prosperous New Year. I also thank you all for visiting my blog and giving valuable comments and suggestions throughout this year.
When we move into a new year, it seems nothing new is happening. May be this is the sign of my growing age which has seen 35 springs and therefore 'New Year' really do not appear new !!
Or may be the year went by was so chaotic that it condensed the enthusiasm of life.
If I recall some of the major headlines which remained in the news in 2008 from Pharma world then it would be :

• Continuing of Heparin case investigations and afterfall.
• Ranbaxy banned for Exporting 28 drug products from their 2 plants after FDA served Warning Letters.
• Ranbaxy acquired by Daiichi Sankyo of Japan.
• Melamine identified in Chinese dairy products.

I wish the coming year comes with lots of good news.

Better Late than Never - GLP on board

Announcement to ammend the Drugs & Cosmetics Act to include Schedule L-I of Rules 74, 78 and 150 E (Third Amendment Rules 2008) giving the pharmaceutical industry time till November 1, 2010 for compliance of Good Laboratory Practices. 

This comes at least 20 years after the last ammendmend made into the US rules in 1987 as 21 CFR part 58 which came into effect in 1979.

Better Late than Never for India.

Under the notification of the Ministry of Health and Family Welfare, Department of Health, No G.S.R.634(E), sections 12 and 33 of the D&C Act, has now inserted 'Good Laboratory Practices' as in Schedule L-I and in Rule 78, in clause (p), and in Rule 150 E, in clause (a). 

With Schedule L-I of Rules 74, 78 and 150 E, all pharmaceutical companies will need to adhere to Good Laboratory Practices (GLP) and have the necessary requirement of premises and equipment. Pharma companies need to speed up to upgrade the systems and there is a need for comprehensive technical sessions on similar lines like Schedule M to create massive awareness on the importance of the compliance.

The news is published in Pharmabiz and can be read here

Recent Changes in GMP Rules

The changes in the GMP rules by the FDA after due consultation from Industry are finally announced. Effective from 8th September, primarily these changes focus on - Plumbing, Aseptic processing, Asbestos filters and Verification by second individual etc.
While a summary of the proposal was already published in details sometimes back in April (click here to read), Krishna Rao has also done a great favour in reviewing and preparing a comparative analysis of these changes in CFR 211. The review by Krishna is published in 'The Pharma Web Journal' and can be read or downloaded in acrobat.

China and its Quality Control

It seems that the quality related issues from China will never end. In fact even when the storm of Heparin was about to settle down, other serious complaints from Chinese made infants milk and other milk related cases started appearing at the global horizon.

As the countries were still in the process of enforcing a ban to import Chinese milk products, another news came that three people died after using the drugs made from Siberian ginseng. There are cases of contraindications when six people from south - western Yuan province administered these injections.

In the early 90's when India started its first generation reforms, the government choose Quality as its element of expanding exports. As a result, many Indian companies initiated the process of obtaining accreditation to ISO Management systems. However, for opening up of world economy, China choose to increase its manufacturing capabilities to reduce cost and capture world market.

It seems in the process of increasing production and focusing only on to the Manufacturing capabilities, the Chinese industry masters left quality and standards way behind.

The result are evident from these incidences - toys made by using hazardous chemical colours and deaths due to sub standard drug products.

National Seminar on “Road Map to the Indian Drug Industry”, 15th – 16th September, 2008

The seminar was inaugurated by the Chief Minister of Andhra Pradesh Dr Y Rajasekhar Reddy by liting lamp along with Dr. K Anji Reddy, Chairman Dr Reddy's Laboratories Limited. Dr. K. Anji Reddy was felicitated by Chief Minister by presenting a shawl as a souvenir.
Speakers in the seminar from different disciplines of Drugs & Pharmaceuticals industry shared their experiences, thoughts and contemporary trends in the fields of drug discovery, IPR, International developments, Manufacturing, GMPs, SHE, IT and Automation.
The most inspiring speech was made by Dr K Anji Reddy in which he informed the audience of his experience, efforts and strategies of tilting the export balance of APIs in India’s favor. In his witty style, he narrated how Dr Reddy’s Labs thought of the IPR regime well in advance and prepared for the drug discovery research.
On the second day of seminar, CEO of Dr Reddy’s, Mr. GV Prasad highlighted the importance of sustainability. At the backdrop of world wide financial & business fluctuation, rise and fall of oil prices and capability of Chinese manufacturers, Mr. GV Prasad explained the audience for the available alternatives. Amidst the challenges to the Indian Pharma companies, he shared his innovative idea of ‘seeing quality from different angle’ and therefore, as an effort for this, how Dr Reddy’s is being benefited by a Japanese consultant who is from an engineering industry background. Mr. GV Prasad also informed about the efforts being made by Dr Reddy’s on Strategic Partners side wherein the company is working for the development of their vendors as a win-win model.
The other eminent speakers include APSIDC MD, MR BP Acharya (IAS), Mr. Sam Bob (IAS), Principal Secretary; Ministry of Commerce who explained the general industrial policy of the state and in particular to SEZs which are being developed.
While, Dr. Lalji Singh from CCMB described the challenges and opportunities available through stem cell research, Dr. Venkatswaralu (former Drug Controller General) emphasized on meeting GMP requirements. Dr. Venkatswaralu highlighted the importance of Human Resource vis-à-vis continuous training and development. He underlines the concerns on ambiguities and inadequacies in GMP documents. He asked the forum that how many companies are auditing Chinese manufacturers and suppliers. He wondered that should we also wait for a Heparin type incident to initiate that.
The other important speakers were Dr. Sengupta (Member Secretary, CPCB and Planning Commission), Mr. Kjell Olsen from GTZ, Mr. S. Mani (VP-SHE, Orchid), and Mr. P Shamugama Sundram from TUV and Rajiv Sodhi from Microsoft.
The seminar presented a vista of information. On one side government policies on infrastructural development and support were conveyed, on the other side the challenges of the next decade were discussed. Mr. P Shamugama Sundram from TUV deliberated the latest requirement of REACH certification as per the new European directive 1907/2006. He further explained the difference between MSDS and CSR requirements for chemical industries.

Regulatory Agencies and the End of Innovation

When FDA first published its visionary paper on 21st Century Initiatives, it's purpose was to give direction to the innovation in technology and management for fully (current) grown pharmaceutical industry. Besides this, the other initiatives which FDA and other regulatory agencies have taken, namely PAT, risk based approach and defining quality systems in GMP prespective are all moving in the same direction of innovation and gives logical interpretation of quality systems management. Though much of it has been said, but nothing substantial has moved on the floor - particularly in India!

ICH is primarily engaged in integrating the current global pharmaceutical quality and related philosophies and practices. However, the newly published ICH Q9 and Q10 speaks of something which was already existing into the innovation hungry pharmaceutical industry. The application of 'risk assessment' and 'quality systems' do not offer anything new. My view point on these developments is this, that it is almost a decade after the advent of 'International GMPs' in India, there is nothing new which is emerging. The cross-functional reviews and the system controls like - Change Control, Incidents handling, APQR and CAPA are still living their life to full.

I don't remember any regulatory inspector asking for the risk assessment details for any drug development process till its commercial launch!

The FDAs 21st century approach and PAT also emphasise on automation and innovation, but nothing substantial has really moved on these fronts at least in India. There appears few seminar brochures giving details on discussions on these topics, few articles appearing in prominent international journals - but nothing beyond that. I am not so sure of European and American companies for imbibing PAT into their regular practices.

The same is the fate of Six sigma or Lean management for pharma industry. We live with the concepts and when the implementation comes - we wait for the regulatory compulsions to arrive.

The question here is - why so many thoughts but no applications ? Have we reached the saturation in terms of implemneting quality systems? Does too much of expectations are distancing the innovation ?

US FDA in India - So What !

The fear of Audits is still alive! Even after at least 3 decades since the first Pharmaceutical facility was audited in India from US FDA, the nervousness to face a FDA inspection has not ended. Even the big Indian companies with good track record have to prepare for the audit much in advance. The audit exercise can only be compared with a father preparing for the marriage of his only daughter. He has to ensure that the marriage party gets a grandeur treatment and leaves the place with complete satisfaction.
However, in this process, the complete focus of a company is not on the quality of products being manufactured or quality systems, but on how to successfully appease the visiting auditors. This, therefore, takes a narrow approach which undermines the ethos of quality philosophy.

Now the recent news that FDA is planning to open their regional offices in India or China is creating hype in industry.

After all our long relationship with FDA (in facing large number of audits) has still not taught us anything new. Even the 21st centry approach, the vision documents from FDA seems to be irrlevant. There are no lessons learned from our past experiences.
And so is the worry that FDA is planning its base in your own city.

Break from Blogging

That was a hectic period. I have taken a break from blogging, but shall comeback soon !!

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Forthcoming - Acquasition of Ranbaxy and future of Regulated Companies in India.