INTRODUCTION:

The quality of the pharmaceutical products must be maintained to provide a standard product to get approval from the FDA for its marketing. Hence in order to produce a standard product that is of good quality, the pharmaceutical industry must follow the rules and regulations¹ as mentioned in the authoritative books and recommendations at national or international levels. This review has a brief description of some of the important parts of the 21 CFR, which are covered to have a better understanding of the rules which are needed to be followed in the pharmaceutical industry^2,3.

The general and the permanent rules which the executive departments and the agencies of the federal government publish in the Federal Register are codified in Code of Federal Regulations. It is broken down into 50 titles that cover major categories governed by federal law. Each title has chapters that often includes name of issuing agency. The various regulatory topics are covered in portions that are further separated into each chapter. At least once a year, each book of the Code is amended, and new editions are published quarterly. Title 21- Food and Drugs is composed of nine volumes. Title 21 CFR covers various areas of regulations for Food and Drugs which are used, imported, and supplied in the US along with Cosmetics, medical devices, diagnostic equipment, radiation devices, etc. It is subdivided into Chapters consisting of numerous parts and subparts which gives detailed rules for the areas covered. Some of the parts which are important and used in the pharmaceutical industry for regulation are discussed in detail.

Subchapter A General:

Volume I: Some of the important parts in Volume I include the following.

Part 11 Electronic Records; Electronic Signatures:

Title 21 CFR Part 11 states that “scope of Part 11 Electronic records and electronic signatures is to guarantee that the electronic records and the electronic signatures can be trusted as much as the paper records and the ink signatures, which are accepted by USFDA in place of handwritten signatures, initials.” This part is applicable to all the electronic records which are created, maintained, archived, modified, retrieved, or transmitted, under any records requirements that are used for regulatory purposes with one exception: Part 11 does not apply to the paper records that are sent electronically (such as email attachments). This part also informs that USFDA will accept electronic signatures to be equivalent to the full handwritten signs, initials, and other general signings as required by agency regulations where the industry can prove, typically via computer system validation, that electronic signatures comply with Part 11 unless the paper records are specifically required. The FDA may inspect the computer systems (hardware and software), the controls, and related documentation that are maintained in accordance with this section. It also states that the records which are not submitted to FDA can be stored as the electronic records and those which are submitted to the FDA need to comply with Part 11 to be prepared as electronic forms. This part includes the definitions of various terms like Agency, Open systems, Closed systems, Biometrics, etc.

Figure 1: Advantages of Part 11 Electronic signatures and electronic records.

The organization must prove Authenticity, Confidentiality, Integrity, Irrefutability of the Electronic records, and validate the systems which are used to produce the electronic records and electronic signatures. It should maintain records, store the documentation, and regular audit trials are carried out including device checks. Along with these, the workflows of the computer, authority checks and the personnel qualification requirements, personnel accountability, and document control are defined which are to be followed by the organization. The electronic record must have the information related to the electronic signature along with printed name of the signer, the date, and time of the signature, and meaning of the signature (e.g., content is accurate, the format is correct, data calculations were verified). The electronic records must be properly linked with the electronic signatures which are connected to them forever and which cannot be copied, excised, or otherwise transferred to falsify any electronic record by ordinary means. The electronic signature is unique to each individual and identity is verified before use. The electronic signatures are authenticated with unique User identification codes and passcodes/passwords, along with periodical changes of the passwords. All the mentioned particulars are the requirements as mentioned in detail in Part 11 Electronic recordsand the electronic signatures, which are to be complied in order to be submitted to the USFDA^4-7.

Part 50 Protection of Human Subjects:

It contains 4 subparts. Subpart A, B, C and D. In subpart A, the scope states “This part is applicable to all clinical studies that fall under the FDA's purview which are under the Federal Food, Drug, and Cosmetic Act, also includes the experimental studies that support requests either to examine or marketing authorizations for goods that fall under its scope, including foods, dietary supplements, products with health or nutrient content claims, infant formulas, foods, and color additives, medical devices that are used for humans, drugs meant for human use, the biologicals, and electronic products.” Definitions of various terms that are mentioned in Informed consent⁸.

The section 50.20, the general necessities for informed consent include information on how the informed consent is to be obtained by the clinical investigator from the potential human subjects. Legally effective informed consent is a prerequisite that is to be obtained by the clinical investigator for a human being to be intromitted as a subject in the research. The investigator can seek such consent from the prospective subject or representative only by their will to participate or not and not by applying any force upon them. There must be enough time to be provided for them to take the decision whether to participate or not. The information which is provided to the subject or the representative must be in language that they understand and easy-to-comprehend terms and words must be used⁹. There must be no informed consent either in oral or written form which includes any language which is not-understandable by the subject may waive the subject’s legal rights.

Figure 2: Benefits of Informed Consent.

The other sections include detailed information about the exception from the general requirements and the exceptions from the informed consent requirements for emergency research. It includes subjects in research when there is an emergency like the subjects present in a life-threatening situation and no other existing treatment is useful or beneficial. There can be an exception from the requirement of informed human consent when there is sufficient data available from the non-clinical and preclinical studies showing the efficiency and safety of the treatment which is going to be used in the clinical investigation to treat the human subjects. Other than the mentioned, this section covers detailed information on different kinds of situations under which informed human consent is not a first priority. This authority and reviewing of the data for conducting the research without seeking consent from the subjects is the responsibility of the Institutional review board and each and every clause and situation is assessed before taking such decisions.

Next section 50.25 includes Elements of informed consent. It discusses the details about the purpose, duration, description of procedures that will be followed, foreseeable risks to the subjects, benefits that can be expected, and alternative procedures which may be advantageous to subjects. It also lists out the statement that participation of the human being in research as subject is voluntary and denial to participate will not cause any penalty to the subject and the subject may discontinue or withdraw from research at any period. Other than these elementary requirements of informed consent, detailed supplementary elements are also described.

The next section 50.27 deals with the documentation requirements of informed consent. Generally, informed consent must be in writing which is approved by the IRB along with a sign and date by the subject or legally authorized representative of subject at time of the consent. A duplicate of the same is given to the individual who is signing the form. When a short form of consent is presented orally, there must be one witness, along with the approval of a written summary by the IRB which is stated to the subject or representative of subject. 50.50 details the duties of IRB. Some of them are reviewing the clinical investigations in which children are involved and providing approval only to those which satisfy the criteria as mentioned in 50.51, 50.52, and 50.53. The additional sections in Subpart D describe the requirements and statements for the children to be used as human subjects in clinical investigation. Subsequent sections 50.51 – 50.56, give various details about how the obtain assent from the children and their guardians’, requirements of consent in situations with the investigations involving minimal risks and potential benefits and probable effects after use.

Part 54 Financial disclosure by clinical investigators:

Scope of this part is that it is applicable to any applicant who submits covered clinical studies along with marketing applications for human medication, biological products, and devices. This part describes in detail about the requirements of the financial disclosure for the Certification. It also includes detailed requirements for evaluation of the agency of financial interests, along with the maintenance and retention of records¹⁰.

Part 58 Good laboratory practice for non-clinical laboratory studies:

Subpart A-General Provisions:

The scope of this part is that it suggests good laboratory practices for the experimental investigations done in the nonclinical laboratory which supports the submissions for research for products or marketing permits of products that are regulated by the FDA¹¹. It includes various food products, additives including color, animal food, drugs used for human and animals, devices used for humans, biologicals, and the electronic products. The definitions sections include definitions of various terms.

The general requirement for the applicability for studies performed under grants includes the notification to consulting laboratory or the contractor that facility is a part of a nonclinical laboratory in which experiment is going to be conducted by the sponsor which is to be reviewed by or submitted to the FDA¹². This must be in compliance with the provisions as mentioned in part 58 of 21 CFR. The inspection of the testing facility for the records and specimens maintained is carried out by any authorized employee of FDA for reasonable times. In case of refusal by the testing facility for inspection by the FDA, it will not consider it as a nonclinical laboratory.

Subpart B—Organization and Personnel:

The general and detailed organization and personnel requirements are described in subpart B. The personnel requirements include the education, experience, and training of the individual who is employed in the conduct or supervision of the nonclinical lab. The data on the training and experience of the personnel present along with the job description is maintained in the lab. Adequate members of the personnel must be present for the correct conduct of studies. Proper sanitation and health condition along with suitable clothing is a prerequisite for the personnel who encounter the test/control articles and test systems, to prevent any type of contamination. If any illness has occurred to the individual, the same should be reported to the immediate supervisors and the individual must not be included in the experimental procedures to avoid any disruption in the study which may result in the unwanted effect on the study¹³.

The testing facility management requirements must include a designated study director and a QAU¹⁴. The identity, the strength, stability, uniformity, and the purity of the control and test articles or mixtures must be assured before use. The proper functioning and the requirements of the laboratory must be understood and followed along with the documentation. The overall responsibility of study director is the conduct and assurance that the protocol must be followed. The analysis along with its interpretation and reporting and documentation of the results is also the responsibility of study director. The review of the recorded and verified data of the observations, following the protocol and GLP (good laboratory practices) requirements is also a duty of the study director.

The quality assurance unit is independent unit which is responsible for the supervision of the studies conducted in the nonclinical lab requirements like the equipment, facilities, personnel, methods, records, practices, etc which are needed to be in compliance with the regulations. It also is responsible for the maintenance of various documents like master schedule sheet, copies of protocol and records of inspection along with sign, date, and other requirements are mentioned in detail in this section. Inspection of the laboratory at regular intervals and reinspection if required to assure the veracity of the study and the submission of this data along with the status of the studies to study director and the management at periodical intervals is also an obligation of the QAU (quality assurance unit)¹⁵. The documentation of all the steps is a must in the nonclinical laboratory.

Subpart C—Facilities:

The general and detailed requirements of the facilities for a nonclinical lab are described in detail in subpart C. The size of the laboratory must be appropriate with divisions for the conduct of each activity in the experiments which do not produce any adverse effects on the conduct of study. The animal care facilities must include an adequate number of rooms for different species, different projects, routine housing of animals, isolation, quarantine, diagnosis, and treatment for control of diseases. Facilities for disposal of animal waste and the sanitary storage of the same must be present. Animal supply facilities with areas for storage, feed, supplies, bedding, and equipment should be provided. For the prevention of contamination, there must be separate rooms for test and control articles as mentioned in detail in the section 58.47. Section 58.49 deals with the requirements related to the laboratory operation areas which states that there must be separate spaces for performing routine and specialized methods as required by the lab studies. For archiving, storage and retrieval of the specimens and the raw data from the completed studies, there must be separate space provided.

Subpart D—Equipment:

The design of the equipment which is to be used in the laboratory studies must have an adequate capacity that can function according to the laid protocol and the same must be in located suitably where it is easy for operation, handling, and cleaning purposes. For the calibration of the equipment used, written SOPs (Standard operating procedures) must be provided near the location of the equipment. Records with details of calibration, inspection and/or standardizing operations must be kept in place.

Subpart E—Testing Facilities Operation:

Detailed SOPs are laid down in section 58.81 related to the testing facilities, the animal room preparation, care of animals, storage, management, method of sampling, receipt, identification, observations of test system, lab tests etc. Laboratory manuals must be present. Labelling of reagents and solutions used in laboratory is a prerequisite for its identification, concentration, and expiry date details. Animal care section discusses the details of the SOPs to be followed for the feed, storage, housing and handling, for care of the animals. Isolation procedures, diagnosis, treatment and quarantine methods are described.

Subpart F—Test and Control Articles:

The description of the test and control article covers details like identification, its strength, the purity and the composition of tests and control, documentation of methods of synthesis, and derivation are to be documented. The process of labelling of marketed formulation and in house preparations are discussed in detail in the section 58.105. 58.107 section deals with test and the control article handling procedures and requirements in detail.

Subpart G—Protocol for and Conduct of a Nonclinical Laboratory:

Details about the protocol, its objectives, and methods for the conduct of study, with a descriptive title, the purpose of study statement, test and control articles identification with its code number, CAS number. The name of the sponsor and related details of the conduct of the study, and the testing facility address are some of the requirements.

Subparts H and I are [Reserved].

Subpart J—Records and Reports:

The detailed records and report-keeping requirements are covered in this subpart. Reporting of the data related to the nonclinical laboratory study results must include final report with all the details like name, address of the facility, Objectives, and procedures, Statistical approaches, The test and control articles, Stability of the test and the control articles, explanation of the methods used, description of the test system used along with number, species, sex, age, body weight, etc of animals used. The description of the dosage, regimen, route of administration, and duration is also included. The detailed other requirements of the study director, individual scientists involved, their signs with dates, etc. are described in this section. Sections 58.190 Storage and the Retrieval of the Records and Data and 58.195 Retention of Records have the data related to keeping records, maintaining, storage, and the retention of the same and its detailed requirements. The conditions under which they should be stored and retained and the documentation requirements etc. are all covered.

Subpart K—Disqualification of Testing Facilities:

Under the various sections of this subpart, the goal, the grounds for disqualification, notice, measures which should be taken on disqualification, a substitute or additional actions to disqualification, and reintroduction of a disqualified testing facility are all covered in detail.

Volume II:

Subchapter B Food for Human Consumption:

It covers laws and rules that pertain to things like food labeling, common names for non-standardized foods, nutritional quality guidelines to foods, foods for special dietary uses, infant formula requirements for current good manufacturing practise, quality control processes, quality parameters, reports and records, and notifications, infant formula, permit control, and inevitable contaminants in food for human consumption and food packaging material. Aside from these significant regulatory areas, Part 110 Current Good Manufacturing Practise in Manufacturing, Packing, Labelling, or Holding Operations for Human Food and Part 111 Current Good Manufacturing Practise in Production, Packaging, Labelling, or Storing Operations for Dietary Supplements both address current good manufacturing practises. Parts 100 through 169 are included.

Volume III:

It is under Subchapter B and contains regulations covering Food additives, its petitions, which are added directly to foods for human consumption, secondary additives of food, Indirect food additives, Irradiation in production and handling of the food, substances that are recognized as safe, dietary supplements, etc. which are divided into parts 170 to 190, whereas parts 191-199 are reserved.

Volume IV:

Subchapter C Drugs: General

Part 210 Current good manufacturing practices in manufacturing, processing, packing, or holding of drugs:

In order to ensure that a drug complies with the act's requirements for safety, has the identity and strength, and meets the quality and purity characteristics¹⁶ that it aims to have or is represented to have, this chapter contains minimum current good manufacturing practises for the procedures that are used in, and the premises or controls to be used for, the manufacture, processing, packing, or holding of a drug¹⁷. If the drug or pharmaceutical product fails to comply with these regulations then it is rendered contaminated under section 501(a)(2)(B) of the act and the responsible person and drug is subject to regulatory action. Part 210 is applicable to parts 211, 225, and 226 of the 21 CFR which are related to the regulations for good manufacturing practices for a drug; parts 600 with 680 for the biological products and part 1271 for the human cell, tissue, or cellular-based product or tissue-based product. An investigational drug that is to be used in phase 1 of the clinical trials, then its production is exempt from the compliance of part 211 regulations, whereas in phase 2/3 of the clinical trials when it is made available for use by the sponsor for the sponsor, then it must be in compliance with part 211. Section 210.3 contains definitions of various terms.

Part 211 Current good manufacturing practice for finished pharmaceuticals:

Subpart A has the scope and the definitions sections included in this part are the same as part 210. Subpart B has regulations related to the responsibilities of the quality control unit (QCU), stating that there must be separate unit that must have written procedures for the testing with all the available materials and facilities to perform them and all the other responsibilities. The authority to either approve or discard the components, the containers and closures, materials: in-process or packaging, labeling, and the drug products along with the authority of rejecting or approving the final drug products, pharmaceutical formulations which are produced, processed, and held in the company lie with the QCU. The qualifications of a personnel who is engaged in the various steps, and processes in the industry are mentioned in section 211.25¹⁸. Educational requirements along with training sessions which are conducted by a qualified individual (s) periodically are the requirements as mentioned. The personnel responsibilities are described in detail in section 211.28. The clothing requirement and good sanitation and health habits are necessitated along with immediate reporting of any illness to the immediate supervisor. Some areas have authorized entry which is to be followed by the personnel. The consultant’s prerequisite along with the maintenance of the records with details of the names, addresses, and qualifications and is also mentioned. The consultants must have sufficient education along with experience and training and can advise on the different processes like manufacturing, packing, processing, or holding of the drug product.

Subpart C contains regulations for the features that must be present in the buildings and facilities. The features for the design and construction of the building must be of suitable size, and must be located such that cleaning and maintenance is easy. There must be adequate space for proper placement of the all equipment and materials to avoid mixups and any form of contamination between different products, components, containers, labeling and other production processes. There must be defined areas for the operations of different steps like identification, holding, storage, manufacturing, packaging, labeling, quarantine, aseptic processing etc. Proper lighting should be provided in all the areas. Adequate ventilation with control over air pressure, dust, humidity, and the temperature should be present. Air filtration units including prefilters must be used¹⁹. Other detailed requirements are mentioned in 211.46. There must be standard potable water supplied with a continuous positive pressure. It must be meet the requirements of Environmental Protection Agency’s primary drinking water regulations as per part 141 of Title 40 CFR. The sewage and trash disposal must be done in a sanitary manner. The washing and toilet facilities must be provided which have both cold and hot water, air driers, detergent or soap etc. which are in easy accessibility. Buildings must be in good sanitary condition without any infestation with birds, rodents, insects, etc. The separation and disposal of the waste must be proper. The written sanitation procedures must be followed by all temporary or permanent employees. The procedures must have the detailed steps, schedules, equipment, and the use of the appropriate rodenticides, fungicides, etc. must also be in written form. Maintenance of the building should be done such that it stays in good state.

Subpart D Equipment, has the Requirements related to the Equipment design, location, size and its construction are discussed in the 211.63 and 211.65 sections. The construction material used must be such that surfaces which get in contact with any components or materials must be non-reactive, non-additive, or non-absorptive which affects the identity, mentioned strength, quality, safety, or the purity of the drug product²⁰. The cleaning of the equipment and its maintenance must be done according to the written procedures and at periodic intervals of the time according to the cleaning schedules. The automatic, the mechanical and the electronic equipment which include computers, or other related systems used in the manufacturing and other steps in the facility then they must be regularly inspected, calibrated or verified according to the written procedures. Input and output of the computer must be checked for the accuracy and only authorized personnel are given access to changes that are instituted in the master production or control records. Backup files must be maintained wherever required. The filters which are used in the manufacturing and other steps of the processing should not release the fibres into the products.

Subpart E contains the GMP for the Control of the Components and Drug Product Containers and the Closures. It contains general requirements like the written procedures on how to do the identification, storage, handling etc. of the containers, closures and other packing materials which are to be followed. The storage should be such that it must avoid contamination and easy cleaning, maintenance and inspection can be done. There must be a specific code for each group of containers for drug products or components etc. The requirements for the receipt of the untested components, storage of those is listed out in section 211.82. Section 211.84 contains detailed rules for the testing of the components, product containers, and closures for either their approval or rejection. After the testing is done, how the approved components are to be used in stated in 211.86. Retesting of containers, closures, can be done at appropriate for testing the basic characteristics of identity, its strength and level of purity and quality. The section 211.89 tells what to do with the rejected products stating that those must be kept in quarantine when not suitable for use. Section 211.94 deals with the detailed practices for the containers and closures used for the drug products. The basic requirement includes that the containers must be non-reactive, non-additive and non-absorptive in nature as it may change the identity, decrease the safety, increase levels of impurities and the strength of the drug may get altered from the established requirements. The containers must protect the product present inside from external factors and should be cleaned, sterilized, and processed as per the nature of the drug. The gas containers and the closures must fulfill the conditions as mentioned in detail in the section 211.94.

Subpart F has Production and Process Controls includes the written procedures for the production and the process control²¹ are to be designed for the assurance that the products are identified properly, have prescribed strength, good quality, and have a specified level of purity. Any changes should be properly drafted and reviewed and must be later approved by QCU²². Charge-in of the components are discussed in section 211.101. The production of the batch must be done such that it should have not less than 100% of the labeled amount of the API. The steps like weighing, measuring, and subdividing must be done appropriately and supervised. The detailed requirements are present the section. The calculation of the yield at suitable phases of the complete manufacturing process must be done by one person which is verified by second personnel independently. The identification of the equipment, processing lines, containers etc. must be proper and indicate the phase of manufacturing and their contents. Identification number must be assigned for major equipment²³. Written procedures for the in-process testing of the materials and drug products must be followed to guarantee the uniformity of the batch and the integrity of the products ²⁴. Control procedures must be established for the in-process controls examinations and tests which will help monitor the outputs and for performance validation of the processes. Other list of tests which are to be performed are present in the section 211.10. The time limits must be set to perform each stage in the manufacturing to maintain the required quality, deviation may be acceptable if it does not compromise on the quality. Steps must be followed to control the microbial contamination²⁵ by keeping separate written procedures for both products which require sterilization and which do not require sterilization. Reprocessing of the batches which do not pass the specifications should be done as per the written procedures, such that they can conform to the specifications or standards and under the review of quality control unit.

Subpart G covers the Packaging and Labeling Controls which has different sections which has details on how to do the tasks like examination of materials and their usage criteria in 211.122, in section 211.125 the issuance of the labels, packaging and the labeling operations in 211.130, tamper-evident packing for the Over-the-counter drugs and their requirements in section 211.132, 211.134 inspection of the drug products, and the expiration dating in mentioned is section 211.137. Subpart H Holding and Distribution of the various components and drug products are described under sections Warehousing practices and the procedures for the distribution. For both activities, written processes must be used and followed. Quarantine and the storage of pharmaceutical items under the right conditions of temperature, relative humidity, and light are both included in warehousing. The oldest medication items in the batch must be delivered first, and the product distribution process must be done in a way that makes it possible to recall products quickly in the event that this becomes required.

Figure 3: Components of Good Manufacturing Practices

This Subpart I Laboratory Controls has in detailed general requirements section which has the basic and descriptive information that is to be followed. The establishment of the specifications, plans, procedures for testing and other lab controls should be drafted, reviewed and get approval from the QCU. The documentation of the performance must be done. The controls are necessary for the characterization of quality of the products manufactured. The testing and the release of the product is done before the distribution which is also known as the quality control testing of the products ²⁶. Each batch from the lot is determined for its satisfactory fulfilment of the final specifications without any microbial contamination and the sterility and pyrogen testing must also be done for the required products. The written procedures for the method of the sampling with the number of units taken from each batch along with its acceptance criteria is established and which must be met by the pharmaceutical product. The documentation of the validation of the procedure followed must be done to get the accurate, reproducible, and sensitive results. Rejection of the products which fail to meet the specifications is done and the reprocessing of the same must be done which should be further used only when the established standards are met. The stability testing of the products must be done with a written procedure which can test the characteristics of the product. This is done to establish the storage conditions and the expiry date for the manufactured product. The testing must be done by using an adequate number of batches and along with the basic stability studies, accelerated studies must also be conducted to support the tentative expiry dates. The section 211.167 covers special testing requirements for sterile and/or pyrogen-free products, ophthalmic ointments, and controlled-release products.

The procedure for reserving the samples is covered in section 211.170. One sample from each batch as a representative of that batch should be retained and the sample quantity must be twice as that necessary for the testing of the product. The retention time of the various products containing different types of the active ingredients like the radioactive drug or OTC drugs etc. is mentioned in detail in this section. Other requirements of testing for the stability and storage conditions are also described in detail. The laboratory animal requirements for testing the components, products, in-process materials must be in compliance with the standards and have suitability for their intended use in the testing along with the maintenance of the records. Section 211.76 covers the topic of penicillin contamination in the facility and how to avoid or reduce the cross-contamination. The testing of the non-penicillin drug for traces of penicillin must be done and if found that product must not be marketed.

The procedure on what to do with the returned drug products is mentioned in the section 211.204 of Subpart K the returned and Salvaged drug products²⁷. The identification and labeling of the returned products must be as such and if doubts are present with any identification of the product the destruction of the products must be done. Records must be maintained for noting dosage form, quantity returned, name and potency of the product as mentioned on the label, batch number, reason, the date of the disposition and the ultimate disposition of the returned product. The drug product salvaging topic is covered in 211.208. Drug products when stored under extreme conditions must not be salvaged and returned to the marketplace when the conditions are met. The conditions include evidence from the lab tests that the products pass the test for the established specifications. The evidence from inspection that the premises of storage of the drug products have not been the subject to improper storage due to disaster or accident.

Subpart J has detailed requirements for the Records and Reports that are to be maintained in the industry. The general requirements of the records that should be maintained are listed out in the section 211.180²⁸. The records related to the production; distribution should be kept for a year after the expiry date of product. The records of the components, containers, closures must be kept for 1 year after the expiry date. Other detailed requirements must be maintained for the inspection purposes are mentioned in the section. The cleaning of the equipment and use log records must be maintained where written records which has the details like date, product, time, and the batch number of product processed are required. The records of the cleaning and the maintenance of the equipment are also required. Further sections 211.184, 211.186, 211.188, 211.192, 211.94, 211.196 and 211.198 contains other detailed record requirements. The procedure on what to do with the returned drug products is mentioned in the section 211.204 of Subpart K the returned and Salvaged drug products. Records must be maintained for noting the dosage form, quantity returned, name and potency of product as mentioned on the label, lot number, reason of the return, the date of the disposition and the ultimate disposition of the returned product. The drug product salvaging topic is covered in 211.208. Drug products when stored under extreme conditions must not be salvaged and returned to the marketplace when the conditions are met. The conditions include the evidence from the lab tests that the products pass test for the established specifications. The evidence from inspection that the premises of storage of the drug products have not been the subject to improper storage due to disaster or accident.

Volume V: It has Subchapter D: Drugs for Human Use, it has various parts related to detailed requirements for drugs intended for human use, a list of all types of the drugs and category of the drugs under which to fall into.

PART 312 Investigational New Drug Application:

This part contains the processes and the requirements which govern the use of the investigational new drugs (IND]. These requirements are for the IND which are submitted and reviewed by the FDA. The exemptions are also mentioned in this section 312.2. The next section contains the various definitions and the interpretations which are used in this part. Section 312.6 has the requirements on how to do the labeling of the IND. The requirements and procedure for the promotion of the IND and the charging of it is described in sections 312.6 and 312.7. Subpart B covers the various sections on the INDA - IND Application. The requirements for an IND in section 312.20 states “the sponsor should submit the IND to FDA when sponsor who intends to conduct the clinical investigation with the IND. section 312.21 covers the phases in an investigation.” FDA has given the opportunity to submit the IND in one or more than one phase. The phases of an untested drug are divided into three phases. the phase 1 must be conducted in 20-80 patients or in normal human volunteers and generally they are conducted to determine metabolism, and the pharmacological actions of drug in the body and the side effects if any to calculate the early efficacy of the drug. In Phase 2 controlled clinical trials are conducted to assess the effectiveness and patients with the condition or disease are included with a number up to several hundred. Phase 3 conducts clinical studies with up to several thousands of patients. These studies are conducted in both controlled and the uncontrolled trials, and conducted after the primary evidence that the drug is effective.

Figure 4: Contents of an Investigational New Drug (IND) Application.²⁹

The general principles of the IND submission are mentioned in the section 312.22. section 312.30 has the requirements for any protocol amendments, Information amendments in section 312.31, 312.32 has detailed requirements for the safety reporting of the IND, 312.3 annual reports, and 31.28 has requirements of the withdrawal of IND. Subpart c is related to the administrative actions that are required for the IND³⁰. The stages of the actions that are released from the review board are mentioned in sections in detail like the comment and advice on an IND as in 312.41, 312.42 which has clinical holds and the request for the modification, the termination details in 312.44, inactive status in 312.45, meetings and dispute resolution in 312.47 and 312.48 respectively. Subpart D deals with the roles of the sponsors and the investigators. Subpart E has the detailed requirements for the drugs that are intended for the treatment of dangerous and severely debilitating illnesses. Other miscellaneous requirements like the import and the export details, foreign clinical studies that are not conducted under an IND, the availability of the public disclosure of the data, the address for the correspondence, and the guidance documents. The requirements for experimental usage in the laboratory research animals or in vitro studies are covered in Subpart G ³¹. Subpart I is concerned with the increased access to investigational pharmaceuticals for therapeutic use, whereas Subpart H is reserved.

Volume VI: It has Subchapter E Animal Drugs, Feeds, And Related Products which has all the related requirements of the animals, their feed, drugs used, new animal drugs, food contaminants avoidable and unavoidable etc.

Voulme VII: It has Subchapter F Biologics and Subchapter G Cosmetics. Parts 600-699 has all the rules and regulations related to the biological product, its licensing, cGMP for biological products, general requirement of the product standards etc. whereas Subchapter G covers parts 700-799 which has the rules and regulations of the labelling requirements, registration, filling of the products ingredient composition statements etc.

Volume VIII: It has 4 subchapters, Subchapter H covers Medical Devices, Subchapter I include Mammography Quality Standards Act, Subchapter J has Radiological Health related rules, Subchapter K prescribes rules for Tobacco Products and Subchapter L has Regulations Under Certain Other Acts Administered by The Food and Drug Administration. Each subchapter has in detail requirements of the mentioned topics.

Volume IX: It has chapters II and III, Chapter II Drug Enforcement Administration, Department of Justice, and Chapter III—Office of National Drug Control Policy which has parts 1300-end.

CONCLUSION:

This review article has covered briefly the rules and regulations of parts 11, 50, 54, 58, 210, 211 and 312 of the Title 21 CFR. Title 21 CFR has other parts which may be useful in other areas. To obtain any pharmaceutical product with specified strength, quality, purity, and identity it is important to follow various rules in the manufacturing and processing of the product in the pharmaceutical industry. Compliance to these parts also increases the chance of the industry to get the approval from the FDA of the product manufactured for the marketing.

CONFLICT OF INTERESTS:

None.

ACKNOWLEDGEMENT:

We are thankful to our Principal, Prof. M. Sumakanth and Faculty of Pharmaceutical Analysis of RBVRR Women’s College of Pharmacy for giving us this opportunity to write this work.

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Received on 24.06.2025 Revised on 16.10.2025

Accepted on 18.12.2025 Published on 02.07.2026

Available online from July 15, 2026

Asian J. Res. Pharm. Sci. 2026; 16(3):255-264.

DOI: 10.52711/2231-5659.2026.00038

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Figure 4: Contents of an Investigational New Drug (IND) Application.29

Figure 4: Contents of an Investigational New Drug (IND) Application.²⁹