Regulating the Safety of Drug Products

Pharmaceutic Labs adheres to the highest manufacturing standards under the law for preparation of drug products. The Code of Federal Regulations (CFR) or specifically 21 CFR Part 211 details what an outsourcing facility must do to manufacture safe drug products. We abide by all standards regulated by the Food and Drug Administration (FDA). All finished pharmaceuticals are manufactured using specific requirements or Current Good Manufacturing Practices for identity, strength, quality, and purity. 

The summary below outlines key points of the regulations. Every aspect of drug production is considered for quality control.

21 CFR Part 211

21.11 Responsibilities of a Quality Control Facility 

All components, containers, closures, in-process materials, packaging material, labeling and drug products, with production records available for review, including a full investigation of any errors that have occurred.

The Quality Control facility is an adequate laboratory. All procedures or specifications impacting the quality of the drug product are approved/rejected. Responsibilities are in writing and shall be followed.

211.25 Qualifications of Staff

All personnel have the education, training and experience to uphold quality control. Everyone who supervises personal has the education, training and experience to provide assurance for drug quality. There will always be an adequate number of qualified personnel at the facility.

211.28 Staff Attire and Conduct

All personnel wear sterile clothing and protective apparel. They practice good sanitation and health habits in the facility, including the use of limited access areas. Sick personal are never allowed in manufacturing areas.

211.34 Outside Consultants

Any consultant hired has sufficient, education, training and experience to advise on the subject matter. Records stating the name, address and qualifications of consultants are kept on site.

211.42 Design and Construction Features

The facility is maintained to ensure proper cleaning and operation with adequate space to perform all operations in defined areas.

211.44 Facility Lighting

Proper lighting is used in all areas of the facility to perform required tasks.

211.46 Ventilation, Air Filtration, Air Heating and Cooling

Adequate ventilation is used in the facility, including equipment to control micro, dust and air-pressure with air filtration.

211.48 Plumbing

The facility has a potable water supply with continuous positive pressure meeting the EPA requirements. The plumbing system is free of defects with drains of adequate size and includes an air break prevention design.

211.50 Sewage and Refuse

All trash at the facility is disposed of in a safe and sanitary manner.

211.52 Washing and Restrooms

The facility has adequate washing areas with hot and cold potable water, soap and detergent, with air dryers near working areas.

211.56 Sanitation

The facility is maintained in a cleanly state, free of any pests. Written procedures on cleaning schedules, methods, equipment and materials are followed, along with rodenticides, insecticides, and fungicides. All efforts are made to prevent contamination.

211.58 Maintenance of the Facility

The facility is maintained in a good state.

211.63 Equipment Design

The equipment is of the appropriate design, adequate size and optimal location to support operations, cleaning and maintenance. 

211.65 Equipment Construction

The equipment is constructed to not be reactive with product. All lubricants/coolants do not come into contact with product to alter their quality.

211.67 Maintenance of Equipment

The equipment and utensils are cleaned, maintained and sanitized to prevent contamination and malfunctions. Written procedures are established for cleaning and maintaining equipment and utensils used within the manufacturing process arena and are stated in maintenance, cleaning, sanitizing, and inspection records.

211.68 Equipment Calibration

All of the automatic, mechanical and electronic equipment, computers, etc. used in manufacturing areas are routinely calibrated, checked and inspected per a written program with retained records, including change controls, input/output verification, and back-ups.

211.72 Filters

Filters do not release fibers into drug products. If fiber-releasing filters are necessary then additional 0.22 micron max porosity are used or 0.45 if manufacturing conditions are necessary.

211.80 Procedures

Written procedures for receipt, sampling, approval, and rejection are maintained. All products are handled and stored to prevent contamination. Bagged or boxed items are stored off the floor. Each contain of items has an ID with code for each lot received and its status.

211.82 Receipt and Storage of Untested Products

All items are inspected to ensure they are correct, as well as to check for damage or contamination. Items are quarantined until inspected and released.

211.84 Approval or Rejection of Product after Testing

Each lot must adhere to Quality Control procedures before being released. Product sampling is based upon criteria. Samples are cleaned when necessary, obtained in a way to prevent contamination, processed with sterile equipment when needed, without subdividing, and include the samples’ ID with lot #, container, and date. Containers must indicate samples were taken.

211.86 Use of Components

All components are approved. FIFO is used when possible (1st in – 1st out).

211.87 Retesting of Approved Components

All components are retested after stored for extended periods or after exposure to air, heat and other conditions that might compromise its quality.

211.89 Rejected Components

All rejected components are ID’d and placed into quarantine.

211.94 Drug Product Containers and Closures

All drug product containers and closures are not reactive, additive or absorptive, affecting the quality of the product. They provide protection from external factors that could contaminate or deteriorate the product. They are clean and appropriate for use. Written standards are followed to test the cleanliness, sterilization and non-pyrogenation of containers.

211.100 Written Procedures and Deviations

Written procedures for production as well as process control ensure drug products have the specified identity, strength, quality and purity to be Quality Control approved. All procedures are followed and the execution of production and process control functions are recorded at the time of completion. All deviations are recorded and justified.

211.101 Charge-in Components

Batch formulations are intended to produce 100% active ingredients. All components transferred to non-original containers are identified with: name, item code, receiving or control number, weight or measurement in the new container and the batch for which the component was issued, including name, strength and lot number. All weighing operations are supervised as a Quality Control released component, with correct weight or measurement per batch record and are properly identified on the container. All component batches are verified by a second person.

211.103 Calculation of Yield

Actual yields and percentages are calculated against theoretical yields at the end of each phase of production. These calculations are verified independently by a second person.

211.05 Equipment Identification

All containers, processing lines, and major equipment used during production are identified to indicate the contents of a batch and phase, if required. Major equipment is uniquely identified and shown in the batch record to indicate the specific equipment used.

211.110 Sampling and Testing of In-Process Materials and Drug Products

Procedures indicate in-process controls and tests in order to validate performance and monitor output, including: tablet or capsule weight variation, disintegration time, adequacy of mixing to assure uniformity, dissolution time and rate and clarity, completeness or the pH of solutions. In-process specifications are consistent with final specifications. In-process materials are tested for ID, quality, strength and purity. They are accepted or rejected by Quality Control. Rejected material is quarantined.

211.11 Time Limitations

If needed, time is limited for completing each phase. Deviations from time constraints are only allowed if quality is not compromised and such actions are documented and justified.

211.113 Control of Microbiological Contamination

A written procedure addresses the prevention of microorganisms in drug products that are not required to be sterile. Another written procedure addresses the prevention of microorganisms in sterilized drug products, including the process for sterilization.

211.115 Reprocessing

A written procedure describes a system for reprocessing non-forming batches and steps taken to ensure reprocessed batches conform to standards and specifications. Reprocessing will not occur without review and approval for Quality Control.

211.122 Materials Examination and Usage Criteria

Written procedures are followed for receipt, ID, storage, handling, sampling, testing, etc. All materials are sampled and examined. Those materials not meeting specifications are rejected. Records for each shipment are retained (receipt, examination and acceptance or rejection documentation). Labeling materials for each product are stored separately. Access to special production areas is limited to authorized personnel. Obsolete and outdated materials are destroyed. Gang printing is not used unless differentiated by size, shape or color. Labels are cut with dedicated lines for each product and strength. Electronic equipment are used or visual inspections, using a second person to verify. Printing devices are monitored.

211.125 Labeling Issuance

Strict control is used when issuing. Issued materials are compared to a master. Quantities are reconciled (used and returned product equals issued product). All excess materials with lot number are destroyed. All returned materials are stored in a way to prevent mistakes. Procedures detail the control of issuance.

211.130 Packaging and Labeling Operations

Materials are physically or spatially separated to prevent mix-ups or cross-contamination. Filled but unlabeled products are set aside. Groups have an ID to prevent mislabeling. The manufacturing history of product is available through a lot or control number. The batch record includes an examination for the correctness of labels. Packaging and labeling facilities are inspected before and after labeling operations and are reflected in the batch record.

211.132 Tamper-resistant Packaging Requirements for OTC Human Drug Products

OTCs for retail sale except for throat lozenges, dermatological products, as well as insulin and dentifrice products are tamper-resistant or they are considered adulterated. Tamper-resistant products have one or more barriers or indictors that show visible evidence or breached integrity. Two-piece hard gelatin capsules require two tamper-resistant packages unless capsules are sealed by a tamper-resistant means. A minimum of one tamper-resistant feature is used for sealed, two-piece gelatin capsules. Products have a prominent statement indicating to the consumer the tamper-resistant feature is still visible if the feature is breached or missing. If necessary, the “Request for Exemption from Tamper-Resistant Rule” petition is used, containing the name of the drug product or drug class, the reason for exemption, the alternative or steps taken for reducing tampering and other information justifying an exemption. OTCs are subject to NDA requirements and therefore the FDA must be notified of packaging changes.

 211.134 Drug Product Inspection

Packaged and labeled products are inspected to assure correct labeling. A sampling of units is collected and inspected for correct labeling. Results of the inspection are recorded in the batch record.

211.137 Expiration Dating

The expiration date of products is determined by stability testing. The storage conditions on labeling are also determined by stability testing. Reconstituted products have an expiration date for both reconstitution and unreconstitution. All labels have expiration dates. Homeopathic drugs are exempt from labeling. Allergenic extracts labeled “No U.S. Standard of Potency” are also exempt. New products for investigational use are exempt as well if they meet stability specifications in their clinical investigations. OTCs are exempt if labeling does not have a dosage and they are stable for three years.

211.142 Warehousing Procedures

Drug products are quarantined prior to Quality Control release. Storage conditions are provided that will not affect the drug products adversely, such as light, temperature, and humidity.

211.150 Distribution Procedures

The oldest products are distributed first. Deviation is permitted if it is temporary and appropriate. A system is in place to readily recall distributed product if necessary.

211.160 General Requirements

The quality unit reviews all specifications, standards, sampling plans, test procedures and any changes. Deviations are recorded and justified. Lab controls are scientifically sound. Determine conformance to specifications with components, in-process and sampling. Calibration is performed.

211.165 Testing and Release for Distribution

Each batch must meet final specifications prior to release. Lots are free of objectionable microorganisms. Sampling and testing is described in SOPs. Accuracy, sensitivity, specificity and reproducibility of test methods are established and documented. Lots not meeting specifications are rejected.

211.166 Stability Testing

Stability is done and results are used to determine storage conditions and expiration dates. A written program includes: sample size, test intervals, and storage conditions. Reliable, meaningful and specific test methods are always used.

211.170 Reserve Samples

Reserve samples are taken with a representative of each lot. Twice the quantity is produced for a full battery of tests with regards to the final product and the Active Pharmaceutical Ingredients (API).

211.173 Laboratory Animals

Lab animals are maintained and controlled.

211.176 Penicillin Contamination

Penicillin is controlled in a separate facility.

211.180 General Requirements

All documents are retained at least 1 year after the expiration date or certain OTCs, 3 years after distribution. All documents are readily available for review and can be copied. Data is evaluated at least annually. Procedures have been established to assure that management is notified of investigations, recalls and FDA issues.

211.182 Equipment Cleaning and Use Log

Records of major equipment cleaning, maintenance (except routine) and use are kept.

211.184 Component, Drug Product Container, Closure and Labeling Records

Records are made on components, containers, closures and labeling, including the name of supplier, supplier lot #, receiving code and date received. Records on the results of tests and individual inventory are also kept.

211.186 Master Production and Control Records

Records are made by one person and checked by another (prepared, dated, signed with full signature). They include: the name and strength of a product and the dosage form, the name and weight measure of API, the total weight of each dosage unit, the complete list of components, an accurate statement of weights with reasonable variations and theoretical reconciliation.

211.188 Batch Production and Control Records

Batch records are maintained for each lot, including dates, person responsible for work, RM lot #, the weights used, any test results, inspections, yields, specimens of labeling, sampling performed and any investigations made.

211.192 Production Record Review

Records are reviewed by the quality unit and all issues and resolved. They include all investigations performed.

211.194 Laboratory Records

Lab records include complete data from all tests including a description of the sample received, a statement of each method, a complete record of all data with graphs, charts, the initials of the person doing test and dates, the initials of the person checking and dates, the calibration data maintained, and the stability records maintained.

211.196 Distribution Records

Distribution records are maintained, including to whom, where, what, and the quantity.

211.198 Complaint Files

Complaint files are maintained with investigations performed that include the name of the product, the lot number, the name of the person who filed the complaint, the nature of the complaint, and the reply.

211.204 Returned Drug Products

Returned products are identified and held. If conditions of return or storage are in doubt, then an investigation follows. All procedures are in writing.

211.208 Drug Product Salvaging

Product subjected to improper storage conditions due to disaster or accident will not be salvaged unless tests show proof of quality. Evaluation of conditions includes finding evidence that indicates product was not exposed to harsh conditions.

 Www.Compliance-Insight.com provides a summary of 21 CFR Part 211. For the full legislation, refer to http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=211