International Journal of Trend in Scientific Research and Development (IJTSRD) Volume 5 Issue 6, September-October 2021 Available Online: www.ijtsrd.com e-ISSN: 2456 – 6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1461 Good Manufacturing Practice (GMP) Guidelines (Eudralex-Volume 4) Mr. Rajesh. L. Dumpala 1 , Mrs. Lakshmi Prasuna. R. Dumpala 2 1Research Scientist, Department F. & D. (MS&T), Alembic Research Centre, Vadodara, Gujarat, India 2Assistant Professor, Department of Pharmacy, Sumandeep Vidyapeeth University, Vadodara, Gujarat, India ABSTRACT The basic rules in any good manufacturing practice (GMP) regulations postulate that the pharmaceutical manufacturer must maintain appropriate documentation and records. Documentation helps to build up a detailed interpretation of what a manufacturing function has done in the past and what it is doing now and, thus, it provides a base for planning what it is going to do in the future. Regulatory evaluators, during their inspections of manufacturing sites, often devote much time on examining a company’s documents and records. Effective documentation boosts the visibility of the quality assurance system. KEY WORDS: GMP, 21 CFR, Part 210 and 211, Documentation, Regulations Agencies How to cite this paper: Mr. Rajesh. L. Dumpala | Mrs. Lakshmi Prasuna. R. Dumpala "Good Manufacturing Practice (GMP) Guidelines (Eudralex-Volume 4)" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456- 6470, Volume-5 | Issue-6, October 2021, pp.1461-1472, URL: www.ijtsrd.com/papers/ijtsrd47639.pdf Copyright © 2021 by author (s) and International Journal of Trend in Scientific Research and Development Journal. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0) HISTORY OF GMP
US patented medicine, first produced in 1861 in Chicago by former magician John Austen Hamlin and his brother Lysander Butler Hamlin
Primarily sold and used as liniment for rheumatic pain and sore muscles
Was also advertised as a treatment for cancer, pneumonia, diphtheria, earache, toothache headache and hydrophobia.
Made of 50% - 70% alcohol containing camphor, ammonia, chloroform, sassafras, cloves and turpentine and was said to be usable both internally and topically In 1916, Lysander's son Lawrence B. Hamlin, was fined $200 under the 1906 Pure Food and Drug Act for misbranding it as a ‘cancer drug’ IJTSRD47639 International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1462 WHAT HISTORY TEACHES US…… PHARMACEUTICAL DISASTERS Thalidomide Tragedy: Thousands of children born with birth defects due to adverse drug reactions of morning sickness pill taken by mothers Contamination: Sulfathiaziole tablets contaminated with phenobarbital- 300 people died/injured…. GOOD MANUFACTURING PRACTICES (GMP) DEFINITION: GMP is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standard appropriate to their intended use and as required by the marketing authorization. Good Manufacturing Practices (GMPs) are regulations that describe the methods, equipment, facilities, and controls required for producing:
Human and veterinary products
Medical devices
Processed food Usually see “cGMP” – where c = current, to emphasize that the expectations are dynamic. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product. These regulations, which have the force of law, require that manufacturers, processors, and packagers of drugs, medical devices, some food, and blood take protective steps to ensure that their products are safe, pure, and effective. Require a quality approach to manufacturing, enabling companies to minimize or eliminate instances of contamination, mix-ups, and errors. Protects the consumer from purchasing a product, which is not effective or even dangerous. GMP regulations address issues including record keeping, personnel qualifications, sanitation, cleanliness, equipment verification, process validation, and complaint handling. In short GMP makes the difference between nearly right and exactly right. WHY GMP?
Final testing of the product cannot ensure the Quality efficiency and safety.
Final testing may always not detect contamination, error, etc.
Conformance to the predetermined specification.
To minimize contamination eg:- microbial contamination.
To eliminate error.
To produce product of consistent quality.
Government requirement.
Ensure quality product.
Reduce rejects, recalls.
Satisfied customers.
Company image and reputation. CODE OF FEDERAL REGULATIONS (CFR):
It is the Portion of FDA.
The collection of final regulations published in the federal register (daily published records of proposed rules, final rules, meeting notices, etc.
Divided into 50 titles.
Current regulations of GMP appear in part 210 (title 21) of code of federal regulations published by USFDA. International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1463 REGULATIONS AGENCIES GUIDANCE DOCUMENTS 21 CFR, PART 210 AND 211 CURRENT GOOD MANUFACTURING PRACTICE AN QUICKVIEW OF THE FDA REGULATIONS Introduction CFR – Code of Federal Regulations (Administrative Law) – 50 titles Title 21 – Food and Drugs 210 CGMP in Manufacturing, Processing, Packaging or holding drugs – General 211 CGMP of Finished Pharmaceuticals International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1464 Part 210 General Status of the regulations
Regulations set forth are “minimum” requirements!!!!
Covers manufacturing, facilities and controls for • Manufacturing, processing, packaging or holding of a drug product
Failure to comply will render the drug to be adulterated • The person who is responsible for the failure to comply shall be subject to regulatory action. Applicability:- Applies to drug products for human use Definitions
Batch:- A specific quantity of drug/material intended to have uniform character and quality produced under a single manufacturing order form during the same cycle of manufacture.
Component:- Any ingredient intended for use INCLUDING those that may not appear in such drug product
Drug Product:- Finished dosage form
Fiber:- Any particulate with a length at least 3 times to its width
Active ingredient:- Any component intended to furnish pharmacological activity
Drug:- Drug is defined by the Act as any compound that has effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure or function of the body of man or animals
In-process material:- Any material fabricated, compounded, blended or derived for use in the drug product.
Manufacture, processing, packing or holding includes:- Packaging and labeling, testing and quality control of drug products
Quality Control:- Any person or unit designated by the firm to be responsible for duties relating to QC
Representative Sample:- Samples drawn on rational criteria intended to accurately portray the material being sampled 21 CFR Part 211 Subpart A General Provisions Subpart B Organization and Personnel Subpart C Buildings and Facilities Subpart D Equipment Subpart E Control of Components and Drug Product Containers and Closures Subpart F Production and Process Controls Subpart G Packaging and Labeling Control Subpart H Holding and Distribution Subpart I Laboratory Controls Subpart J Records and Reports Subpart K Returned and Salvaged Drug Products Subpart A General Provisions Scope
Minimum requirements
Applies to drugs for human use Definitions
Those set forth in 210.3 are applicable Subpart B Organization and Personnel 211.22 Responsibilities of QC The QC unit shall have adequate laboratory facilities
They shall have the responsibility for approving/rejecting all procedures or specifications impacting the quality of the drug product
Responsibilities shall be in writing and shall be followed. 211.25 Personnel Qualifications
Everyone shall have the education, training and experience to do their jobs.
Everyone who supervises those people shall have the education, training and experience to assign functions to provide assurance for drug quality.
There shall be an adequate number of qualified personnel. 211.28 Personnel Responsibilities
Wear clean clothing and protective apparel
Practice good sanitation and health habits
Limited access areas
If you are sick – do you belong in the area 211.34 Consultants
Shall have sufficient education, training and experience to advise on the subject matter.
Records maintained stating the name, address and qualifications of consultants. SUBPART C – BUILDINGS AND FACILITIES 211.42 Design & Construction
Any building shall be maintained to facilitate cleaning, maintenance and proper operations
Adequate space
Operations performed in defined areas
Receipt, storage, holding, etc.
All operations
Penicillin operations in separate area 211.44 Lighting
Adequate lighting provided International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1465 211.46 Ventilation
Adequate ventilation
Adequate equipment for control of environment (micro, dust, air-pressure)
Air filtration provided 211.48 Plumbing
Potable water supplied under continuous positive pressure
System free of defects
Potable water meeting EPA requirements (40 CFR, Part 141)
Drains of adequate size
Back-flow prevention 211.50 Sewage and Refuse
Dispose of trash, sewage and other refuse in a safe and sanitary manner 211.52 Washing and toilet facilities
Adequate washing facilities shall be provided
Hot and cold potable water
Soap and detergent
Air dryers or single-service towels
Easy access to working areas 211.56 Sanitization
Facilities shall be maintained in a clean and sanitary condition
Free of rodents, birds, insects
There shall be written procedures on cleaning schedules, methods, equipment and materials
Shall be written procedures for rodent ides, insecticides, fungicides
Facilities shall be maintained in a good state of repair SUBPART D – EQUIPMENT 211.63 Equipment design, size and location
Equipment shall be of appropriate design, adequate size and suitably located to facilitate operations, cleaning and maintenance 211.65 Equipment construction
Equipment material of construction not be reactive with product.
Lubricants/coolants shall not come into contact with product to alter the quality of the product Equipment cleaning and maintenance
Equipment and utensils shall be cleaned, maintained and sanitized to prevent malfunctions and contamination
Written procedures shall be established for cleaning and maintenance of equipment, utensils.
Records shall be kept of maintenance, cleaning, sanitizing and inspection. Automatic, Mechanical & Electronic Equipment
Automatic, mechanical and electronic equipment, computers, etc. used in the manufacturing area shall be routinely calibrated, checked and inspected as per written procedure with retained records of calibrations, inspections, etc.
Computers systems documentation and validation documentation shall be maintained.
Computer systems electronic records must be controlled including records retention, backup, and security. 211.72 Filters • Shall not release fibers into drug products
If fiber releasing filters are necessary • Additional filtering using 0.22 micron max porosity • 0.45 if manufacturing conditions so dictate
Use of asbestos-containing filter is allowed only after proving to FDA safety or effectiveness is not compromised SUBPART E – CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURE 211.80 General Requirements
Written procedures shall be made and followed for receipt, sampling, approval, rejection.
Handle and store in a manner to prevent contamination
Bagged or boxed items shall be stored off of the floor and be adequately space for cleaning and inspection
Each Lot/container shall be identified with code for each lot received and status (quarantined, approved, rejected). 211.82 Receipt and Storage
Shall be examined visually for appropriate labeling as to contents, container damage/seals broken, contamination, etc upon receipt.
Materials shall be quarantined until tested and released. 211.84 Testing and Approval/Rejection
Materials shall be withheld from use until tested and released for use by Quality Control.
From each lot shall be sampled upon appropriate statistical criteria.
Samples collection
Clean the container if necessary
Collect the samples in designated area to prevent contamination
Samples shall be identified with lot#, date, and done by, etc.
Containers must show samples were taken International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1466
Samples shall be tested for at least one identification test.
COA of manufacturer shall be acceptable provided by at least one specific identification test by establishing vendor evaluation.
Any lot that does not meet the specifications shall be rejected. Use of Approved components
Materials shall be used/issued in FIFO.
Deviation of FIFO shall be permitted, if temporary and appropriate. Retesting
Materials shall be retested after storing a long time might be have adverse affect on quality due to exposure to air, heat etc. 211.89 Rejected materials
Rejected materials shall be stored under designated area to prevent the use for manufacturing. 211.94 Drug product containers and closures
Provide protection from external factors that could contaminate or deteriorate drug
Shall not be reactive, additive or absorptive as to adversely effect product
Clean and suitable for use
Specification and test methods shall be written and followed. SUBPART F – PRODUCTION & PROCESS CONTROLS Written procedures; deviations
Written procedures shall be established and followed for Production (BMR) and process controls (in-process, Intermediate spec.)
Process control functions shall be recorded at the time of performance.
Any deviation from the established procedure shall be recorded and justified. Charge-in of components
Each batch formulation should attempt to make 100% of specified active ingredient
Components for manufacturing shall be weighed, measured, or subdivided as appropriate and should be verified by second person.
QC released/approved
Containers are identified & Weight/measurement is correct per batch record
When a component is transferred to a non- original container, it shall indicate – Name, item code,– Receiving/control number,– Weight/measurement in new container, – Batch for which component was issued including name, strength and lot number, Each component added to the batch shall be verified by the second person 211.103 Calculation of yield
Actual yields and percentages of theoretical yield shall be determined at the conclusion of each stage of manufacturing, processing, packaging, or holding of the drug product.
Such calculations shall either be performed by one person and independently verified by a second person. 211.105 Equipment identification
Storage containers, processing lines, and major equipment used during the production shall be properly identified.
Major equipment shall be identified by number or code that shall be recorded in the batch production record to show the specific equipment used. 211.110 Sampling and testing of in-process materials
In-process specifications shall be consistent with final specifications
In-process materials tested for quality, strength & purity & be accepted or rejected by QC
Rejected material shall be quarantined in order to prevent use in Manufacturing 211.111 Time limitations on production
When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the product.
Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented. 211.113 Control of microbiological contamination
Written procedures shall be established and followed to prevent objectionable microorganisms in drug products of non-sterile.
Written procedures shall be established and followed to prevent microbiological contamination into sterile drug products, Such procedures shall include validation. 211.111 Time limitations on production
When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the product.
Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented. 211.113 Control of microbiological contamination
Written procedures shall be established and followed to prevent objectionable microorganisms in drug products of non-sterile. International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1467
Written procedures shall be established and followed to prevent microbiological contamination into sterile drug products, Such procedures shall include validation. 211.111 Time limitations on production
When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the product.
Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented. 211.113 Control of microbiological contamination
Written procedures shall be established and followed to prevent objectionable microorganisms in drug products of non-sterile.
Written procedures shall be established and followed to prevent microbiological contamination into sterile drug products.
Such procedures shall include validation. 211.125 Labeling issuance
Strict control shall be exercised over labeling issued for use
Compare issued materials to master
Reconciliation of labels should be maintain
All excess labeling bearing lot or control numbers shall be destroyed
Written procedures shall be established and followed for the issuance of labeling
Returned materials shall be stored separately to prevent mix-ups 211.130 Packaging and labeling operations
Written procedures shall be established and followed for Packaging and Labeling operations, procedure shall cover the following
Prevention of mix-ups & contamination
Identification and handling of set aside filled but unlabeled product.
Identification of the drug product with a lot or control
Examination for suitability and correctness before packaging operations
Inspection of packaging & labeling facilities to ensure the previous products are removed and cleaned
211.134 Drug product inspection
Packaged and labeled product should be final inspected to assure correct labeling
A sampling of units shall be collected and inspected for correctlabeling
Results of inspection shall be recorded in batch record 211.137 Expiration dating
Expiration date should be determined by stability testing
Label shall be reflect the storage condition determined by stability testing
Expiration date shall be bear on label for the products to be reconstituted and un-reconstituted
Expiration dates must be reflect on labeling SUBPART H –HOLDING AND DISTRIBUTION 211.142 Warehousing procedures
Quarantine of drug products before release by the quality control unit
Storage of drug products under appropriate conditions which may not affect the quality/strength 211.150 Distribution procedures
Oldest products are distributed first.
Deviation is permitted if it is temporary and appropriate
Distribution records should be maintain to facilitate recall if required/necessary SUBPART I –LABORATORY CONTROLS 211.160 General requirements
Written procedure shall be established and followed for specification, test procedures, sampling and scientifically sound.
Any deviation from established shall be recorded, justified
Instruments calibrations should be performed as per procedures and schedules
Instruments which are failed don not use. 211.165 Testing and release for distribution
Every batch should meet the specification prior to release
Sampling and testing plans should be described in written procedure
Validated method should be employed for testing
Any batch, not met the specification shall be rejected 211.166 Stability testing
Stability studies should be performed.
Stability sample should be simulated to the market
Written procedure should be available with the following details
Sample details (Quantity, batch # etc.)
Testing interval
Stability conditions
Stability specifications 211.170 Reserve sample
Representative of each batch sample shall be retained. International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1468
Sample quantity consists of two complete analysis
Sample should be simulated to the market
Sample should be retained up to 1 year after expiration.
Sample should be examined visually once in a year for any deterioration and to recorded 211.173 Laboratory animals
Penicillin controlled in separate facility
If, exposed to penicillin, the product shall be tested for the presence of penicillin. Such drug product shall not be marketed until they complies as per FDA requirements. SUBPART J –RECORDS AND REPORTS
Records shall be retained for at least 1 year after the expiration date
All records or copies of such records shall be readily available for review/inspection
Product quality review should be performed once in a year 211.182 Equipment cleaning and use log 211.180 General Requirements
Equipment usage records should be maintain. 211.184 Container, closure, and labeling records
Records shall be maintain, including
Supplier name and lot number
Date of receipt
Approved/Rejected
Label shall be compared with master 211.186 Master production and control records
Master production and control records shall be maintain
Made by one person and checked by another (prepared, dated, signed –full signature)
Complete list of components
Accurate statement of weights, reasonable variations
Theoretical reconciliation 211.188 Batch production and control records
Batch production and control records shall be maintain, includes
Operation dates & Equipments used
List of materials and quantities
In-process results
Actual yield & Theoretical yield
Deviations
Done by & Checked by sign 211.192 Production record review
Batch records including packaging and labeling, shall be reviewed and approved prior to release.
If any batch failed to meet the specifications shall be investigated and recorded.
The investigation shall extend to other batches … that may have been associated with the specific failure or discrepancy
A written record of the investigation shall be made and shall include the conclusions and follow-up. 211.194 Laboratory records Lab records include complete data from all tests: Description of sample received & Statement of each method
Complete record of all data –graphs, charts
Initials of person doing test and dates
Initials of person checking and dates
Calibration data maintained
Stability records maintained 211.196 Distribution records
Distribution records shall be maintained • Who, where, what, quantity 211.198 Compliant files
Complaint files shall be maintained • Investigations performed • Include name of product, lot number, name of complainant, nature of complaint, reply SUBPART K –RETURNED AND SALVAGED DRUG PRODUCTS 211.204 Returned drug products
Returned products identified and held
If conditions of return or storage are in doubt, investigation is warranted
Procedures shall be in writing 211.208 Drug product salvaging
Product subjected to improper storage conditions due to disaster or accident shall not be salvaged
Unless,
Tests can show everything is OK
Evaluation of conditions indicates product was not exposed to such harsh conditions Eudralex-Volume 4 of "The rules governing medicinal products in the European Union"contains guidance for the interpretation of the principles and guidelines of good manufacturing practices for medicinal products for human and veterinary use PART I- BASIC REQUIREMENTS FOR MEDICINAL PRODUCTS
Chapter1- Pharmaceutical Quality System
Chapter2- Personnel
Chapter3- Premise and Equipment Chapter4-Documentation Chapter5- Production Chapter6- Quality Control Chapter7- Outsourced activities International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1469 Chapter8-Complaints and Product Recall Chapter9- Self Inspection PART II-BASIC REQUIREMENTS FOR ACTIVE SUBSTANCES USED AS STARTING MATERIALS PART III- GMP RELATED DOCUMENTS Site Master File Q9 Quality Risk Management Q10 Note for Guidance on Pharmaceutical Quality System ORGANIZATION AND PERSONNEL
Sanitation and Hygiene-Personnel Hygiene HEALTH
Health Examination for personnel in manufacturing and laboratory areas shall be done at the time of recruitment.
Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products should not be allowed to handle starting materials, packaging materials, in-process materials or drug products until the condition is no longer judged to be a risk. BUILDING & FACILITY International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1470 EQUIPMENT MATERIALS MATERIALS STORAGE International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1471 PACKAGING AND LABELLING CONTROL HOLDING AND DISTRIBUTION COMMON PROBLEMS IN GMP EXECUTION: 1. Organization:
Lack of commitment
Lack of resources for execution 2. Layout & Construction:
No quarantine area
Insufficient environmental monitoring
Cracked floor 3. Equipment:
No calibration
No performance check of balance before use
Rusty
Parts not kept improperly 4. Laboratory Testing:
Poor reference standard keeping
Poor data recording
Reagent with no label 5. Documentation & Recording:
No signature; no countercheck
Improper correction made
No written procedure
Incomplete complaint record
No up-to-date training record
No document review 6. Labelling:
Status not defined clearly
Poor labelling control
Release label not kept securely
Inadequate reconciliation of batch label
Defective equipment with no label 7. Validation:
Insufficient validation
Insufficient raw data
No validation programme International Journal of Trend in Scientific Research and Development @ www.ijtsrd.com eISSN: 2456-6470 @ IJTSRD | Unique Paper ID – IJTSRD47639 | Volume – 5 | Issue – 6 | Sep-Oct 2021 Page 1472 References: - 1. Good manufacturing practices for pharmaceutical. A plan for total quality control by willig. 2. The Gazette of India .Sch – M. 3. The Theory and practice of industrial pharmacy by Lachman. Pg:- 804 4. www.bioscreen.com. 5. Myers, John. Fundamentals of Production that Influence Industrial Facility Designs. Appraisal Journal. April 1994. 6. http://apps.who.int/medicinedocs/en/d/Js5517e/2 0.4.11.html 7. Dumpala and Khodakiya, IJPSR, 2021; Vol. 12(3): 1860-1874. 8. https://www.fda.gov/downloads/drugs/developm entapprovalprocess/smallbusinessassistance/ucm 456370.pdf 9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC 4991121/ 10. https://www.dcvmn.org 11. Mr. Rajesh Dumpala | Ms. Jaini Bhavsar | Mr. Chirag Patil "Quality by Design: A Present to Future Perspective" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-5, August 2020, pp.878-885. 12. Lund, W.: Good manufacturing practices. The pharmaceutical codex: principle and practice of pharmaceutics. London, Edition 12, The Pharmaceutical Press, 1994, 362-397. 13. Nally J. and Kieffer R.G.: GMP compliance, productivity and quality, Interpharm,1998, 465- 466. 14. Nally J.D.: Good manufacturing practices for pharmaceuticals, Informa healthcare USA, Inc., ISBN 10:0-8593-3972-3 & ISBN13:, Edition 6, New York, 2007, 978-0-8493-3972- 1.