Dosage Form Design: Equipment & Components

• Study notes on Dosage Form Design

Subpart D: Equipment

• Each piece of equipment should facilitate use, cleaning, and maintenance through appropriate design and size.
• Equipment surfaces shouldn't interact with processes/products, ensuring no impact on purity, strength, or quality.
• Standard operating procedures (SOPs) must be written and followed for proper use, maintenance, and cleaning of each piece of equipment.
• Equipment/computers in processes must be routinely calibrated, maintained, and validated for accuracy.
• Filters used for injectable drug products must not release fibers into products.

Subpart E: Control of components, containers and closure:

• Processes for identification, storage, handling, sampling, testing, and approval/rejection of product components, containers, and closures must be maintained and followed as written procedures.
• Pharmaceutical chemicals, containers, and enclosure bulk must meet exact physical and chemical specifications that were established with supplier when ordering.
• Raw materials are quarantined and verified through sampling and qualitative/quantitative analysis by quality control unit.
• Rejected components, containers, and closures are identified/controlled under a quarantine system. This prevents use in manufacturing/processing operations.
• Bulk chemicals (APIs) are mainly synthesized in China and India; confirm identity/purity with USP and NF.

Subpart F: Production and Process Controls

• Drug products must have correct identity, strength, quality, and purity via written procedures.
• In-process samples from production batches should be sampled periodically for product control.
• Sampling is performed by production personnel at time of operation and by QC lab staff to ensure compliance with specifications and consistency.

Subpart G: Packaging and Labeling Control

• Issuance of labeling and packaging materials requires written procedures.
• Labeling for each drug product variation (strength, dosage form, quantity) - must be stored separately with identification.
• Outdated labels/packaging materials have to be destroyed and storage area access is limited to authorized personnel.
• Label examination must be done by one person and independently verified by a second person.
• Labels must meet legal requirements for content.
• Each label has to contain expiration dating and the production batch or lot number.
• Stability testing is used to determine expiration date to make sure drug product meets applicable standards when used.
• Homeopathic drug products, allergenic extracts, and investigational drugs are exceptions that must meet standards during preclinical and clinical studies.
• In 1982, consumers of Tylenol died of cyanide poisoning due to tampering on store shelves.
• Tamper-evident package: Contains one or more indicators/barriers; if breached/missing, tampering is visible to consumers (examples: blister/strip pack, seal band, bottle seal, tape seal, aerosol container).

Subpart H: Holding and Distribution

• Written procedures are to be followed for holding and distribution of product.
• Finished drugs are quarantined in storage until released by quality control unit.
• Products are to be stored/shipped under conditions to not affect quality.
• The oldest approved stock is distributed first.
• Distribution control system must allow determination of the distribution point for each lot of drug product, so its recall can be facilitated if necessary.

Subpart I: Laboratory controls

• Requirements include specifications, standards, sampling plans, and test procedures.
• Specifications that apply to each batch of drug product include sample size, test intervals, sample storage, and stability testing.
• Special testing requirements include parenteral, ophthalmic, controlled release products and radioactive pharmaceuticals.

Subpart J: Records and Reports

• Master records of each batch must document each step and must be approved by quality control unit.
• Must be maintained for at least a year following the expiration date of a product batch.
• Equipment cleaning and maintenance logs have to be kept.
• Specifications and lot numbers should be documented for product components (raw materials, container, closure, labeling).
• Production and batch production and control records, production record review, laboratory records, distribution records, and complaint files must be readily available.
• Records of complaints regarding to drug product, along with information regarding the internal disposition of each complaint must be maintained.
• All records must be available for inspection by FDA officials.
• Returned drugs must be identified by lot number as well as product quality.
• Drug products that meet specifications can be salvaged or reprocessed.
• Products subjected to improper storage are not returned to the marketplace.
• Records for all returns include date/reasons for return, quantity/lot number of product, procedures employed for holding/testing/reprocessing, and product's disposition.

Additional cGMP Regulatory Requirements

• Inspection of bulk pharmaceutical chemicals assures all quality standards are met since the quality of finished pharmaceutical product depends on the quality of its components.
• GMP focuses on all elements of chemical purity and quality, including specifications/analytical methods to detect impurities/chemical residues, critical chemical reaction steps, quality of water, handling solvents, effect of scale-up, and stability studies.

Biologics

• Biologic medicines contain substances from living cells/organisms like gene therapies, transplant tissue, recombinant proteins, stem cell therapies, monoclonal antibodies and treat severe diseases.
• The cGMP regulations for biologic products are similar to finished pharmaceuticals.

Medical Devices

• Devices are approved for marketing through premarket approval when shown to be safe and effective.
• Regulations for "good manufacturing practice for medical devices" are similar in organizational structure to those for finished pharmaceuticals and include personnel, buildings, equipment, component control, process controls, packaging/labeling, holding/distribution, evaluation, and records.
• They are subject to reporting adverse events, recall, and termination of approval; include intraocular lenses, hearing aids, intrauterine devices, cardiac pacemakers, clinical chemistry analyzers, catheters, dental X-ray equipment, surgical gloves, condoms, prosthetic hip joints, CT equipment, and wheelchairs.

Objectives cGMP- Part 4

• Distinguish similarity and difference between pharmaceutical manufacturing and extemporaneous compounding.
• Define the types of packaging containers and their properties.

cGMP and cGCP (current Good Compounding Practices)

• Pharmaceutical manufacturing is large-scale production.
• Compounding is professional preparation of prescriptions for specific patients.
• Patient-specific medications are needed because available dosages/strengths are not commercially available, dosage forms aren't commercially available, patients are allergic to excipients, children require flavored liquids, some medications are unstable and need quick dispensing, and home health uses new approaches/concentrations.
• The compounded drug in community pharmacy have required quality and meet standard specifications.
• Standards-setting agencies established guidelines for pharmaceutical compounding in 1990.
• Pharmacy compounding chapters/ monograph were developed/published in U.S. Pharmacopeia–National Formulary (USP-NP). They provide tested, uniform formulation with valid beyond-use dating (Discard after), conditions/practices to prevent harm (including death to patients), microbial contamination, endotoxins, variability, contaminants, and ingredients.
• The Good Compounding Practices are applicable to State-Licensed Pharmacies, developed by the National Association of Boards of Pharmacy, with general provisions, organization, facilities, equipment, component control, written procedures, and labeling control.

Expiration Date vs Beyond-Use Date

• Expiration Date: Date until manufacturer can guarantee strength/safety, determined by FDA, conditions.
• Beyond-Use Date: Date until a compounded prescription is no longer to be used and is determined by pharmacy, and degradation, dosage, container, storage, length, contamination.

Beyond Use Date

• Non-aqueous formulations: no later than the time remaining until the earliest expiration date of any API or 6 months, whichever is earlier.

• Water-containing oral formulations: no later than 14 days when stored at controlled cold temperatures.

• Water-containing topical/ dermal and mucosal liquid and semi-solid formulations: No later than 30 days.

• Proper packaging, labeling, and storage are essential for adequate efficacy.

• A container holds material and may be in direct contact.

Containers

• According to the USP a container holds the material being transported.
• Immediate container: In direct contact with the article at all times.
• Closure is part of the container.
• Depending on intended use, selected qualities tested are: physicochemical properties, light transmission, drug compatibility, vapor transmission, leaching/migration, moisture barrier, toxicity, valve/actuator, sterility/permeation, drug stability.
• USP classifies containers based on ability to protect contents from external conditions.

Containers classifications according to the USP

• Well-closed: protects contents from solids
• Tight-closed: protects contents from contamination by liquids, solids or vapors.
• Hermetic: impervious to air/gas under ordinary conditions; holds sterile preparations for injection/administration.
• Unit-dose package: identification of dosage/error reduction, contamination reduction, better inventory control, management.
• Packaging materials include paper, foil, plastic, or cellophane.
• The packaging of solids is done with clear plastic or aluminum blister wells.
• Opened single-dose container (ampoules+syringes or cartridges) are not resealable to maintain sterility.
• Multiple-dose container is hermetic and allows withdrawal of successive portions without changing strength/quality, commonly called vials.
• Oral liquids may be dispensed in paper or plastic cups/prepackaged and dispensed in small glass containers having threaded caps or crimped aluminum caps.
• Use disposable plastic syringes with rubber or plastic tips.
• Other dosages found in single-unit packages include: suppositories, ointments, and ophthalmic solutions.
• Unit-of-use packaging: Antibiotics capsules and other products are packaged to contain a month's supply and useful for patients taking medications.
• Light-resistant containers (amber glass or opaque plastic) reduce light transmission.
• UV absorbers (Tinuvin) may be added to transparent plastic to decrease transmission of UV rays.
• USP Standards define transmission limits between 290-450 nm so it’s light-sensitive.
• Plastic packaging is the coextruded two-layer high-density polyethylene (HDPE) bottle, which has an inner layer of black polyethylene coextruded with an outer layer of white polyethylene, tablets, and capsules.
• Child-resistant & adult-senior use packaging is a container closure that is significantly opening and harmful to children under 5 .