Aug 26, 2014

Regulatory Records Primer Part 2: Decoding the Requirements for Pharmaceutical Manufacturers


In Part 1 of the Regulatory Records Primer (Decoding the Requirements for Medical Device Manufacturers), I discussed the general requirements and thought processes undertaken by the FDA with respect to regulatory records.  While the drug side has not yet “evolved” to using a quality systems approach to the regulatory requirements, the same basic process holds true.  Following is a discussion on the regulatory records required to be maintained by manufacturers of finished drug products.

Master Production and Control Record (21 CFR 211.186)

To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person.  The preparation of master production and control records shall be described in a written procedure and such written procedure must be followed.
The Master Production and Control Record must be:
  • Prepared, dated, and signed by one person
  • Independently checked, dated, and signed by a second person
Master production and control records must include:
  • The name and strength of the product and a description of the dosage form;
  • The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unit;
  • A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic;
  • An accurate statement of the weight or measure of each component, using the same weight system (metric, avoirdupois, or apothecary) for each component.
  • Reasonable variations may be permitted, however, in the amount of components necessary for the preparation in the dosage form, provided they are justified in the master production and control records;
  • A statement concerning any calculated excess of component;
  • A statement of theoretical weight or measure at appropriate phases of processing;
  • A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation according to 21 CFR 211.192;
  • A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling;
  • Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.

Batch Production and Control Record (21 CFR 211.188)

Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch.  Batch production and control records shall include:
  • An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed;
  • Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including:
  • Dates;
  • Identity of individual major equipment and lines used;
  • Specific identification of each batch of component or in-process material used;
  • Weights and measures of components used in the course of processing;
  • In-process and laboratory control results;
  • Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including:
  • Inspection of the packaging and labeling area before and after use;
  • A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing;
  • Complete labeling control records, including specimens or copies of all labeling used;
  • Description of drug product containers and closures;
  • Any sampling performed;
  • Documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished, including:
  • Identification of the persons performing and directly supervising or checking each significant step in the operation, or if a significant step in the operation is performed by automated equipment under 21 CFR 211.68, the identification of the person checking the significant steps performed by the automated equipment;
  • Any investigation made according to 21 CFR 211.192;
  • Results of examinations made in accordance with 21 CFR 211.134.

Equipment Cleaning and Use Log (21 CFR 211.182)

A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use must be included in individual equipment logs that show the date, time, product, and lot number of each batch processed.  If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence.  In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record.
The persons performing and double-checking the cleaning and maintenance (or, if the cleaning and maintenance is performed using automated equipment under 21 CFR 211.168, just the person verifying the cleaning and maintenance done by the automated equipment) shall date and sign or initial the log indicating that the work was performed.  Entries in the log shall be in chronological order.
The Equipment Cleaning and Use Log must address:
  • Written records for major equipment
  • Cleaning
  • Sanitation
  • Maintenance
  • Use
  • Date, time, product, and lot number processed
If dedicated equipment is utilized, individual logs are not required (assuming sequential log numbering).  The person performing must date and sign/initial logs

Component, Drug Product Container, Closure, and Labeling Records (21 CFR 211.184)

These records shall include the following:

  • The identity and quantity of each shipment of each lot of components, drug product containers, closures, and labeling; the name of the supplier; the supplier's lot number(s) if known; the receiving code as specified in 21 CFR 211.180; and the date of receipt. 
  • The name and location of the prime manufacturer, if different from the supplier, shall be listed, if known.
  • The results of any test or examination performed (including those performed as required by 21 CFR 211.82(a), 211.84(d), or 211.122(a)) and the conclusions derived therefrom.
  • An individual inventory record of each component, drug product container, and closure and, for each component, a reconciliation of the use of each lot of such component. The inventory record shall contain sufficient information to allow determination of any batch or lot of drug product associated with the use of each component, drug product container, and closure.
  • Documentation of the examination and review of labels and labeling for conformity with established specifications in accord with 21 CFR 211.122(c) and 211.130(c)
  • The disposition of rejected components, drug product containers, closure, and labeling.

Distribution Records (21 CFR 211.196)

Distribution records must contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped, and lot or control number of the drug product.  For compressed medical gas products, distribution records are not required to contain lot or control numbers.

Laboratory Records (21 CFR 211.194)

Laboratory records must include complete data derived from all tests used to assure compliance, including:

  • Description of sample, quantity, lot number, sampling, date, date of sample receipt
  • Identification of testing/inspection method
  • Weight/measure of sample used for each test, where appropriate
  • Complete record of all data for each test
  • Record of calculations performed
  • Testing/inspection results and comparison to acceptance criteria
  • Initials/signature and date of individuals performing tests/inspections
  • Initials/signature and date of second verifying individual
  • Records of method modifications and reason for modification
  • Identification of reference standards, reagents, and standardized solutions
  • Records of equipment calibration
  • Records of stability testing

Complaint Records/Files (21 CFR 211.198)

There must be written procedures for handling written and oral complaints and those procedures must include:

  • Provisions for review by the quality control unit
  • Method of determination for need of an investigation
  • Method of determination if complaint is a serious and unexpected adverse drug experience (which is required to be reported)
  • Written record for each complaint, including:
    • Name and strength of the drug product
    • Lot number
    • Name of complainant
    • Reply to complainant
    • Written results of investigation, if performed
    • Reason that investigation was not performed/found to be necessary
Records must be maintained at manufacturing facility or otherwise readily available location.

Production Record Review (21 CFR 211.192)

Production and control records must be reviewed and approved by the quality control unit to determine compliance with procedures.  This review must be performed prior to product release/distribution.  Unexplained discrepancies must be thoroughly investigated and written records of investigation, including conclusions and follow-up activities must be maintained.

Editor's Note:  Part 1 of this series was posted August 21, 2014.

Leslie (Les) Schnoll, J.D., MBA, M.S., RAC, CQP has extensive experience in quality assurance, quality control, auditing, regulatory compliance, management, and microbiology in the medical device, pharmaceutical, and clinical/pre-clinical industries.

He is the principal of Quality Docs, LLC, providing quality and regulatory services to the FDA-regulated and Arizona Department of Health-regulated industries. He is also currently an Instructor in the Master of Science in Regulatory Affairs for Drugs, Biologics, and Medical Device program in the College of Professional Studies at Northeastern University and a Faculty Associate at Arizona State University, College of Nursing and Health Innovation, in the MS Regulatory Science and Health Safety Program. He was most recently the Vice President, Quality Assurance and Regulatory Affairs with the J.T. Posey Company and has held executive positions at ThermoGenesis, Theravance, Solectron, Hill-Rom, Gliatech, Cyberonics, Southern Research Institute, KPMG Quality Registrar, and Dow Corning Corporation. Les has conducted various training programs, audits, and systems development in the United States, Canada, Europe, South America, Russia, Australia, and the Pacific Rim. He may be reached at (623) 889-5707 or fdaquality@yahoo.com. Visit his website at www.quality-docs.org.

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