Tablets Scoring. FDA release its guidance to industry

It was just last month while dispensing a tablet for my wife, which was on a higher dosage, I need to adjust the dosage but realized it was rather difficult to break or split it in two pieces to get it of lower dosage as prescribed by the physician. The difficulty in breaking it was due to the fact, the tablet was not scored.

As it was also film coated, the split or broken piece was to be therefore exposed before consumption in next dosage. The dilemma remained and I tried to take precautionary measures. I knew it and so I did it, but what for those who are unaware of handling split fractions of tablets?

But my dilemma was over last week, when Ashish forwarded the new guidance for industry from FDA. This new guidance is on Tablets Scoring: its nomenclature, labeling and data for evaluation.

A good initiative as usual from the FDA. While the guidance will help people like me who may have to dispense broken tablets. The issues are related to dealing with modified released tablets, stability of split tablet, risks of impurity generation etc.

These are set of guidance’s and criteria for industry on which scored tablets characteristics will be evaluated as part of review process.

The guidance can be downloaded from the FDA site or click here.

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.

Proposed Revision in 21 CFR Part 211

The Food and Drug Administration (FDA) is amending certain regulations as the first phase of an incremental approach to modifying the current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. On Dec 4, 2007, the FDA published changes to FDA's drug GMP regulation (Part 211). This is the first step of a phased approach to modernize GMPs. The revised text will be effective from April 17, 2008, if no significant comments are received before February 19, 2008.

Based on the CGMP Working Group’s analysis, FDA decided to take an incremental approach to modifying parts 210 and 211. This is the first increment of modifications to parts 210 and 211

The major highlights for this revision being the following:

A. Plumbing
B. Aseptic Processing
C. Asbestos Filters
D. Verification by second individual

For details summary, read here:

Summary for Annexure to ICH Q8, Product Development

ICH has released the draft consensus guidelines - the annex to ICH Q8 on Pharmaceutical Development. The much awaited release is in its step 2 of ICH process and was made public in November 2007. This is the second release within ICH step 2 processes connecting ICH Q8. The Earlier draft version of Q8 published in 2004 got wide spread response in the industry circles.
The Annex to Q8 provides further clarifications of key concepts outlines in the core guidelines. Additionally, the annexure also explains the principles of quality by design (QbD). In other words, there are two fundamental concepts which emerge from Q8 as whole – (a) integrated pharmaceutical development and (b) submission of related information’s in common technical document format.

For complete summary of the Annexure to Q8, Read here:

The ASTM E2500 Standards..a go to "V"alidations!!!

The adoption of E2500 standards by ASTM is a go to "V" model approach of Validations?? The E2500 standards are adopted by ASTM committee E55 in May 2007. The E 2500 standards titled as "A Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipments"
As there are aspects of qualification that add value in terms of ensuring the equipment and systems are ready to reliably manufacture a quality product; there are other aspects and documentation practices that clearly do not add this value. The basis of this standards is that the rigid rules that surrounds qualification (as practices today) can detract from its overall effectiveness.
The big change comes in the verification stage during the qualification process of this approach. ASTM E2500 states that verification is "A systematic approach to prove that critical elements acting singly or in combination, are fit for intended use, have been properly installed, and operating correctly". This verification would normally be documented in IQ, OQ and PQ documents however, the new approach just states that the verification approach must be documented. The extent of verification and the level of detail of documentation should be based on risk to product quality and patient safety. This approach also allows more flexibility if the design changes before the final acceptance with GEP change managed by and approved by subject matter expert (generally engineers).
After acceptance, GMP change is managed and approved by Quality. So another key factor of this approach is that things change and as long as they are managed and documented correctly this is acceptable.
While ASTM standard E2500 does much to eliminate the "folklore" wasteful practices such as excessive focus on documentation practices that have come to permeate qualifiaction, it also contains provisions that are not typically part of many projects, or if used, aren't given as much attendion as "GMP requirements", specification and design reviews, risk management and application of good engineering practices.

More information on ASTM E2500 can be taken from here.