Update on Schedule L1 of Drug & Cosmetic Act 1940
IntroductionIn the historical context it had been observed that the laboratory data submitted (for registration of chemicals like drugs, pesticides, and others) to the regulatory authorities were of mediocre quality with respect to study design, study conduct and reporting. Not only this lack of quality, but the detection of outright fraud in such “studies” finally led to the development of formal principles of Good Laboratory Practices.
Around the world, its first official use can be found in the 1972 New Zealand -Testing Laboratory Act, where the ‘(promotion of) development and maintenance of good laboratory practices in testing’ had been made a task of the Council of Testing Laboratory Registration. USFDA published Good Laboratory Practices for non- clinical Laboratories in the Federal Register on December 22, 1978 under the Title 21 of the Code of Federal Regulations as Part 58 (21 CFR 58), and these GLP regulations came into effect on June 20, 1979.In the During the late 1970s and early ‘80s, The Netherlands, Switzerland, UK and Japan formulated their national GLP standards. World Health Organization adopted GLP in its thirty-sixth report in 1999 as Good practices for national pharmaceutical control laboratories . In a view to extend the guidelines for national control laboratories, commercial drug manufacturer’s testing lab and other non- governmental testing houses, WHO issued guidance in WHO Technical Report Series, No. 957, 2010, forty- fourth report as Annex 1: WHO good practices for pharmaceutical quality control laboratories.
Government of India, made GLP mandatory vide G.S.R. 780(E) dated 10th November 2008 under Schedule “L-1” with effect from the 1st day of November, 2010.
The basic purpose of all GLP, developed by WHO or nations worldwide, is to assure the quality, integrity and reliability of the laboratory data so that there is always an mutual recognition of the results among laboratories. Amongst these, there are differences in the strictness (or horizon) of the rules. Here in this article, we limit our focus between the rules laid by WHO versus those of Schedule L1, Drugs and Cosmetics Act, 1940, Government Of India. Effort is maximum to cover the important and noteworthy differences between the two.
1. Applicability :As stated earlier in the Introduction section, WHO clearly states its applicability for non- clinical testing in national control laboratories, commercial drug manufacturer’s testing lab and other non- governmental testing houses. Whereas Schedule L1 is not much clear regarding this. It distinctly applies to QC laboratory of licensed pharmaceutical manufacturers and their loan licensing units and Laboratory of licensed drug testing houses, but its applicability for national control laboratories or biological testing houses is not clear.
2. Hierarchical Requirements:WHO demands the existence of mainly four categories of personnel in a lab, namely lab management, technical management, analyst and technical staffs. The laboratory management will hold overall responsibility for the technical operations. In other words, the technical manager (Hopefully head of technical management and hence technical processes) is a delegated task. The head of laboratory is termed alternately as SUPERVISOR and clearly is intended to do work of laboratory overall management.
laboratory overall managementThere is an additional requirement of a Quality Manager, who will have a direct access to the highest level of management at which decisions are taken on laboratory policies or resources.
The qualification requirements along with roles and responsibilities are clearly defined at every stage in this Guideline.
The hierarchical requirements as per Schedule L1 is represented under figure 3. The qualification requirement of the head of laboratory is only defined; others are desired to possess suitable experience and qualification for their assigned duties. Probably the laboratory itself needs to define its own requirement.
3. Inclusion of new concepts for better lab quality assurance:WHO has introduced a series of new concepts for more reliable testing procedure and data reporting. Indian companies who are interested towards WHO GLP compliance in laboratories need to focus on these additional points:
a)Statistical evaluation of test results:- In case of regular test results, wherever appropriate, the data is to be evaluated statistically to determine whether they are mutually consistent and if they meet the specifications used. For this purpose, t- tests, paired t- tests and f- tests may proof to be useful. Such evaluation will provide confidence on the status of compliance of the data from statistical point of view.
b)Investigation of atypical test results:- Possibly this is aimed towards Out of trend (OOT) test results which may/ may not be within specification , but shows an occasional deviation from the normal trend of result. Regular trend analysis along with 6 control chart can easily detect such results. Other statistical tool like Grubbs' test can be applied for the purpose. Systematic investigation of such result may act as a corrective and preventive action for any failure in the entire testing process/ system.
c)Reporting uncertainty of results:- In case of reporting results of investigative testing, the uncertainty of measurements is to be reported. As normally it is not a practice to repeat each test until there is any occurrence of any out of specification (OOS) or OOT (out of trend) test result, there is always a chance that the data obtained is not a true value. Uncertainty associated with the data needs to be reported as a result which is a measure of dispersion/ precision of the data . There are many ways to evaluate such uncertainty factor. OMCL guidelines are a good reference to identification and measurement of uncertainty.
d)Verification of pharmacopoeia or validated analytical procedures:- It is an usual practice of not performing validation study on pharmacopoeial method. In case of pharmacopoeial procedures, majority laboratories adopt them without performing specificity, accuracy, precision or linearity studies. The equipments, reagents and other parameters available during testing may not provide the desired reliability of result. For example in a tablet formulation an excipient may be such that it may hinder the quantitation of the main ingredient or reagent in use is as such that the result is negatively biased. Without validation studies the answer to these may be not found out. WHO GLP hence recommends performing verification of the pharmacopoeial and externally validated procedures to assure suitability of performance under actual conditions of use. In other words, verification is a cut- short validation process with sufficient scientific justification for the parameters (stated under validation) not being checked.
e)Verification of equipments:- As defined by WHO GLP “ verification of performance is the test procedure regularly applies to a system to demonstrate consistency of purpose”. For example verification of pH meters with standard certified buffer solutions before use, verification of balances using suitable test weights (internal calibration system). WHO GLP recommends a written verification programme for laboratory instruments.
Schedule LI clearly lacks this scientific distinctness.
Related: How to plan for a GMP audit
4. Documentation requirements:Both internal and externally generated records and documents are recommended to be controlled by WHO GLP. For a laboratory , internally generated documents encompasses quality manual (if it is impendent unit), standard operating procedures, specification manual, training manual, etc; whilst the externally generated documents meant here are calibration certificates, audit and inspection reports, certificate of analysis of reagents & other chemicals, etc.
The steps of revision are clearly defined and a Master List identifying current version vis-à-vis distribution is recommended to be established. This is a logical approach which is also recommended by ISO 9001: 2008, as leads to traceability and a good audit trail of the work practices. As these are not mentioned in the Schedule L1 or in Schedule M, installations willing to comply to the national standards only may head towards problem in tracking the changes , reasons and justification for changes, and many other.
Moreover, upon every revision or new inclusion of document, WHO GLP advices to train the staffs and to preserve their acknowledgment of training through signature. This is not mandatory according to Schedule L1.
5. Requirement for premises:For the pharmaceutical manufacturers, this is possibly the most discussed topic after the advent of both Schedule L1 or WHO GLP, as this involves a good investment in constructions and installations. There are few areas which needs to be attention:-
a) Change rooms:- As per WHO GLP, the rest and refreshment rooms are recommended to be separate from laboratory areas. Additionally, changing areas and toilets to be easily accessible and appropriate for the number of users. No such mention is present in Schedule L1.
b) Laboratory environment:- There is mention of air ventilation system that ensures dust free environment in Schedule L1. It also necessitates monitoring of temperature, relative humidity including bio burden in both controlled and uncontrolled area. To put differently, Schedule L1 mandates regular monitoring of particle size and microbial count in the entire laboratory area in addition to temperature and relative humidity . There is no need of strictness regarding the limits of bio- burden or particle as such, except for areas for microbiological laboratory (which needs to be aseptic). As such the entire laboratory will have to be covered with air handling units cum an expensive F- filter in order to block the CFUs and particles as per its own set limits and will have monitor for any aberrant trend. The feasibility of bioburden monitoring in uncontrolled area , particularly in areas of the laboratory where destructive tests are carried out indeed needs a second thought.
WHO GLP is pretty relaxed in this aspect. There is no defined or mandatory requirement. It has recommended that the environmental conditions (lighting, energy sources, T, RH, P, etc.) are to be appropriate to the functions and operations to be performed. Additionally the environmental conditions are to be monitored, controlled and documented. As such, microbial count or particle size monitoring can be skipped in lab areas where it may not be required, for example in areas where analytical tests which are destructive in nature are (test material not returned to the main bulk) are carried out. In such areas, simple air- handling units with not-so- expensive coarse filters (G- filters) can serve the purpose of maintaining temperature and relative humidity only .
c)Space requirement:- Though both WHO GLP and Schedule L1 requires adequate space for storage of documents and records, samples, reference substances, retained samples, gases, equipments, etc, WHO GLP seems more elaborate about the requirements of the storage facilities.
6. Accountability(Liability):Wading through the WHO GLP guidelines, one would find mention of defining accountability for all important functions (sampling, accessibility to documents, reagents handling , instrument handling , standard preparation, etc) of the laboratory processes leading to technical results and conclusions. Defined job responsibilities of not only the personnel involved in storage, sampling, preparations, testing is what is required, but accessibilities to documents, records and standards needs to be well documented as record and authorized. Reporting the identification number of the reference standard or material, identification of the equipment used, specifications, test methods along with the analyst and the supervisor involved in approval and checking surely allows a quick identification of error, if any, and scope for subsequent corrective action.
This requirement is also not clearly stated in Schedule L1. This dictates about assigned duties in a laboratory and authorized personnel for carrying out activities in microbiological lab; no-where there is indicated of a mandatory written down job description for each activities.
7. Supplier’s evaluationA documented system of suppliers and service provider’s evaluation and monitoring is a testimonial of quality assurance of laboratory. WHO GLP strongly recommends this, which includes maintaining a list of approved suppliers, evaluation of critical consumables, supplies and services which affect quality of testing. Even in case of subcontracting of testing, periodic assessment is highly advised. Schedule L1 does not include this.
8. Analytical WorksheetAs stated in the ‘Introduction’ section, one of the reasons for birth and subsequent evolution of GLP is to avoid masking of true data. This can be assured by maintaining a good trail of every data reported. In order to achieve this, Schedule L1 prescripts about erasing a data through a single line upon change along with reporting the reason for change, vis-à-vis identification of the analyst making the change via his signature. Now think of a situation where the analyst tears the page of the worksheet where the original data is reported and does a fresh reporting with the revised data in a new page!! In such a case there wont be requirement of providing justification for change along with accountability. Where lies the traceability then??? For this purpose, WHO GLP recommends that the analytical worksheets should have proper page numbering, including total number of pages (and including annexes). A worksheet containing consecutively numbered pages unquestionably avoids situations as described above. This approach is lacking in Schedule L1.
ResultWHO GLP and Schedule L1, Drugs and Cosmetics Act, 1940 have a common theme of assuring reflectance of the true value of the sample under test. For the purpose, both of these have moved several steps forward w.r.t the recommendations stated under respective “quality control” sections under respective Good Manufacturing Practices. Differences are present in the approach to achieve the motive.
Recommendations made by WHO GLP is much distinct and highly structured. Not only the requirements are clearly defined, suitable references to other guidelines, like ICH, OMCL, etc are also provided. Moreover, adoption of modern approaches as discussed makes it scientifically sound. In comparison to this international guideline, Schedule L1 is brief. In many aspects it is indistinct too. For example, regarding working standards, it dictates a regular monitoring, but nothing is said about situations when during such checking, a non- compliance is observed. Similarly, it has prescribed about investigation of technical complaints, distinct technical problems (at least the frequently encountered ones, like OOS investigations, changes etc) that may arise and their approach for redressal should have been clearly mentioned.
DiscussionAs known to all, stricter the regulations , the more is the expenditure w.r.t staffing, documentation , maintenance and monitoring of required parameters. But as always the regulatory bodies suggest a good quality assurance programme ultimately leads to benefit in all ways, improved data quality, reliability and reproducibility of data, avoiding repetition of studies, mutual recognization of results, and low downtime. In the context of small to medium scale Indian pharmaceutical laboratories (both contractual and manufacturers), it might not be possible to jump to the acumen level at one go. Continued improvement in the rule with adequate time for the laboratories to comply with the changing rules will definitely lead to achieving the purpose.
References:1.Annex 1: WHO good practices for pharmaceutical quality control laboratories , WHO Expert Committee on specifications for pharmaceutical preparations, WHO Technical Report Series, 957, Forty-fourth report.
2.Schedule L1: Good Laboratory Practices, Drugs and Cosmetics (Third Amendment) Rules, 2008, Government of India.
3.Schedule M: Good manufacturing practices and requirements of premises, plant and equipment for pharmaceutical products, Government of India.
4.Drugs and Cosmetics Act, 1945, Ministry of Health, Government of India.
5.Moorthy CK. Current Good Manufacturing Practices, Volume III, 1st ed. published by Center for GMP, September 2006: p. 508-599.
6.Montgomery Douglas C. Introduction to Statistical Quality Control, 3rd ed., John Wiley & Sons Publication; 1996:p.77-119, 127-132.
8.OMCL network of the Council of Europe , Quality Assurance Document, European Directorate for the Quality of Medicines & Health Care, Uncertainty of measurement, December 2007.
9.ISO 9001: 2008: Quality Management System
10.Quality assurance of pharmaceuticals, A compendium of guidelines and related materials, Volume 2, 2nd updated edition, Good manufacturing practices and inspection, World Health Organization: 72.
11.Guidance for Industry, Q2 (R1) Validation of Analytical Procedures: Methodology, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), International Conference on Harmonization, Geneva, November 2005.
Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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