You may please recall that final notification for implementation of GLPs as mentioned in Schedule L1 of Drugs & Cosmetics Rules was published vide Govt. Of India GSR 780 (E) in December 2008 and was made applicable since 01.11.2010. It was probably for the first time in the history of implementation of drug regulations that such a long time has been given by Govt of India for implementation of rules.

You may also recall that draft was published on 13.10.2006 and all objections and suggestions received from the public on the said draft rules were considered by the Central Government before publishing this as final amendment. Schedule L-I which is titled as “Good Laboratory Practices and Requirements of Premises and Equipments” is applicable to licensees under provisions of rules 74, 78 and 150 E i.e. holding licenses in forms 25, 28, 28D & 37.

Sir, after my retirement on superannuation, for past almost two years I have been a part of various seminars & workshops on this subject and meeting people to know from them their information of GLPs in Schedule L1 and status of compliance of different provisions of Good Laboratory Practices. To my dismay more than 95% of affected persons do not know if such a requirement exists. I think for this situation, we only are to be blamed that in past two years the information has not reached them. I feel that drug inspectors under your control must have informed their respective licensees about different provisions of GLPs and ideally you must have ensured full GLP compliance for grant of fresh license in this period.

Government of India through DCG(I) and DCC probably had issued directives that implementation of Schedule L1 is to be ensured since 1st November 2010. I hear that many of you in turn have directed your manufacturers that they should conform to requirements of Schedule L1. I am not too sure if all my ex-colleagues responsible for enforcing conditions of licenses in forms 25, 28, 28D & 37 have gone through the total text of this schedule. I see some not-so-easy-to-fill gaps in compliance of requirements of this schedule in upgrading premises personnel & instruments etc. These are required to be bridged for compliance. I am bringing these to your notice so that you will ensure that manufacturing and testing units under your control comply satisfactorily the requirements of Schedule L1 GLPs. Few of these I am narrating below:

Premises - Requirement of Avoiding Cross Contamination in Labs

To avoid cross contamination, separate self contained lab with independent persons is required for units handling both non-b lactam and b lactam type of products & having a common laboratory. If more such categories are handled, separate labs for each category should be insisted by you. 

Air Supplies & Ventilation in Lab Premises

Now the labs i.e. wet chemistry, instrument rooms etc. are required to be maintained as a “dust free working atmosphere” and it can be achieved only by installation of air handling units and independent AHUs are to be provided. These AHUs should have arrangements of temp. & humidity controls. Separate AHUs are required for microbiology operations and sterility testing and since “bio-burden” is to be controlled in air locks, separate AHUs are to be installed in air-locks too (in schedule it is mentioned that bio-burden is to be maintained in air locks). Now all microbiological operations are to be carried out in “aseptic area”, existing labs are to be upgraded to meet aseptic conditions and more space will be required. Sterility testing area is expected to meet Sch. M requirements, though not mentioned the area has to be same as recommended for aseptic filling – i.e. Grade A area surrounded by Grade B or C, to meet this provision of 3-4 air locks is to be made in case already not existing. Animal Houses, wherever provided, are required to be re-designed for making provisions of “clean and dirty corridors”. Revised plans are to be submitted to your offices and are to be freshly approved

Personnel

The lab in-charge has to be of “high professional standing”, and you, within your organization have to decide on this. Since persons with high professional standing only can be employed as lab in-charge, may be you have to publish list of such persons on your respective websites and in case websites are not active or are not updated regularly, you may have to publish the list on regular intervals for benefit of manufacturers and testing labs.     

Training of analysts has now been made compulsory for all the personnel in laboratory, various types of training, most importantly the proficiency training is required to be imparted and documented. For approving any person as “expert technical staff for testing” probably your office has to ensure this before accepting their application and further your inspecting staff has to ensure this condition while conducting inspections.

For creating all the documents as prescribed, more number of properly qualified and experienced personnel is required. E.g. – preparation of “quality system manual” can be undertaken by someone who understands this document.

Reference Materials & Ref. Standards

We very well know that all “reference materials” are necessary for testing and calibration. This GLP expect us that all such materials are to be traceable to agency authorized by Government of India or any other International body. To ensure compliance of this requirement, Govt. of India (Ministry of Health / Office of the DCGI) has to publish names and address of these agencies so that the agencies can be contacted and reference materials/ calibration standards can be obtained, even-though these will be frightfully expensive. God alone knows that how many commercial organizations will be procuring these even for preparation of their working standards. Your good self knows that EPCRS, BPCRS and USPRS in India are obtained from either from M/s “Promochem” Bangaluru or can be imported directly by the manufacturers. Others cannot import these standards. It may surprise you that “counterfeit reference standards” are in existence in India. (During my tenure as a regulatory officer I have noticed these). Your enforcement officers have to be very vigilant during inspection of laboratories that proper reference materials are only used. 

Internal Audits

Since sections 15 and 16 of Schedule M already deal with this requirement, I do not think there will be gaps in complying this requirement. However, the requirement here have few additions e.g. competence of the person(s) performing internal audits is to be decided by “quality manager” and report of such audits is to be reviewed by “top management”. GLPs here has not specified if audit reports are confidential document or an open one. You in your states or at the level of Govt. Of India will be clarifying this before this is implemented. (Internationally, Internal Audit report is a confidential document)   

There are several other requirements too for implementation of GLP as mentioned in Schedule L1 and all are to be complied with. There are terms which are more confusing   than conveying the requirement e.g. it has requirement that “residual sample” shall be retained in “proper storage condition” for a period of one year after the final report. The word “residual sample” is not to be confused with the control samples. I understand this term as “left over samples after analysis”. There may be 3-4 samples generated from a batch during manufacturing process e.g. in case of tablets granules for moisture and assay, final tablets before packing, core tablets to be released for coating and so on. I have a feeling that importance of this requirement is to support an investigation which may be required at times either by your officers or by the manufacturers themselves. Since this is not clarified further in the schedule, you all have to decide your own terminology for ensuring compliance to support “root-cause” of an OOS noticed. Similarly I feel the terms “equipment” and “instrument” in the schedule are not used with proper care and convey proper requirement. I feel because of usage of these terms there is a feeling (or fear) that all costly instruments are to be provided in laboratories.

There was an effort by some of the organizations to bring these confusing terms / requirements to the notice of the DCGI in New Delhi for necessary clarification and/ or correction. These efforts were not successful as he and his officers felt that requirements are quite clear and there is no scope of clarification. In case you need clarifications, you in your capacity as a member of DCC (and some of you are even member of DTAB) can make another effort and avoid umpteen interpretations by different officers under your control. I am constrained to mention these here, as exercise is on for some time to compare GLP in Schedule L1 with other good laboratory practice guidelines available in the world. I have seen one, where author has compared this one with WHO GLP and his write-up is a critical comparison of two texts.

Schedule L1 GLP requirements are applicable to laboratories attached to all manufacturers covered under rules 74 and 78 of Drugs & Cosmetics Rules, which include manufacture of “medical devices”, “diagnostic reagents”, “surgical dressings such as gauges and bandages”, “disinfectant fluids” and “sanitizing fluids” etc. and hold licenses in forms 25 and 28. These laboratories even though tiny sized, shall be in conformity with all GLP requirements & your officers will be ensuring good compliance in laboratories attached to these manufacturing units also.

On administrative side, I am not too sure if there will be requests from the manufacturers for issue of a separate “GLP Certificate as per Schedule L1” on the lines of “GMP Certificate as per Schedule M” for supplies to government procurement agencies. (This is popularly known as State GMP certificate). In case it will be the case compliance through another inspection is to be verified by your officers, before such certificate is issued.

Further, grant of COPPs under WHO GMP certification scheme will also be effected as it is WHO’s requirement that country’s laws are to be complied with before WHO GMP guidelines are insisted and COPP issued. In full sincerity, all those holding COPPs, their manufacturing sites may be visited once again for ensuring GLP compliance and if this exercise is commenced, there will be additional burden of inspections to your officers. I do not think this will be difficult as many of organization under your control have augmented inspecting officer’s strength considerably and more inspections can be easily conducted. 

Sir, I was compelled to bring this to your kind attention as I have noticed and have a strong feeling that compliance of requirements of Schedule L1 in most of units is at a very low level. Number of regulatory bodies from various countries have been visiting pharmaceutical manufacturing sites in India for registration of pharmaceutical products in their countries and they too at times are dismayed to see a low level of compliance by the licensees under your control. I request you to please ensure good compliance of GLPs for benefit of all concerned and I am sure you through enforcement officers will soon and definitely do this.

(The author is Dy. Drugs Controller (I), retired Mumbai -91, kplbhargava@yahoo.co.in)