Comprehensive Guide to cGMP Regulations and Pharmaceutical Manufacturing

cGMP

Current Good Manufacturing Practices; regulations governing the manufacture, processing, packing, and holding of drugs to ensure safety, identity, strength, quality, and purity.

Purpose of cGMP

To ensure drugs are consistently manufactured and controlled according to appropriate quality standards.

cGMP documentation

Requires accurate and complete written records documenting process performance and product quality.

cGMP and marketed drugs

cGMP regulations apply to the manufacture of marketed drugs; they are not generally exempt simply because a drug is being manufactured for clinical use.

cGMP and preclinical/Phase I drugs

The statement that cGMP is not required for drugs manufactured for preclinical or Phase I trials is false; appropriate manufacturing controls still apply.

Current Good Manufacturing Practices phrase

The phrase "current Good Manufacturing Practices" appears in the 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act.

21 CFR Part 210

Contains general cGMP regulations for drugs, including minimum requirements for methods, facilities, and controls used in manufacturing, processing, packing, and holding.

21 CFR Part 211

Contains FDA cGMP regulations primarily covering the manufacture of finished pharmaceutical drug products.

ICH Q7A

Guidance concerning Good Manufacturing Practices for active pharmaceutical ingredients (APIs).

Finished pharmaceutical drug products

Final dosage forms of drugs intended for administration to patients, such as tablets, capsules, injectables, and elixirs.

API

Active Pharmaceutical Ingredient; the active substance responsible for producing the intended pharmacological effect.

Component

Any ingredient or material used in the manufacture of a drug product, including materials that may not appear in the marketed drug product.

Raw material

Material used during manufacturing; a component is a broader term that can include materials used in production that may not appear in the final product.

Inactive ingredient

An ingredient other than the active pharmaceutical ingredient that is included in a drug product.

In-process material

Material that is currently being processed or is between manufacturing steps and is not yet the finished drug product.

Finished dosage form

The final form of a drug intended for administration, such as a tablet, capsule, injectable, or elixir.

In-process blend

A mixture still undergoing manufacturing and therefore not a finished dosage form.

21 CFR 210 quality requirements

Drug manufacturing must ensure the product has the quality, identity, purity, and strength that it claims to possess.

Quality, identity, purity, and strength

The four characteristics specifically identified in the cGMP requirement for drug products.

Batch number

A unique combination of letters and/or numbers used to identify a specific drug batch.

Purpose of batch number

Allows the history of manufacture, packing, holding, and distribution to be traced and facilitates recall of a problematic batch.

Batch number and labeling

Batch identification is information associated with drug labeling and traceability.

Batch number misconception

A batch number is not the year a company's CEO obtained a business degree; it is an identifier for a particular drug batch.

21 CFR Part 211 vs ICH Q7A

Part 211 mainly covers finished drug products, while ICH Q7A provides GMP guidance for APIs.

Phase III manufacturing

During Phase III, companies commonly demonstrate that they can manufacture consistent lots, place product in stability programs, and prepare for FDA pre-approval inspection.

Three lots

At least three lots/batches are generally manufactured with consistent quality and evaluated in a stability program for an NDA.

Stability program

A program used to determine how drug product quality changes or is preserved over time under specified storage conditions.

Phase III lead optimization

Lead optimization is not normally a Phase III manufacturing activity; it occurs earlier in drug development.

Pre-approval inspection

FDA inspection of a manufacturing facility before approval to evaluate compliance with applicable manufacturing requirements.

Quality unit

An independent unit responsible for overseeing the quality system and ensuring appropriate quality decisions are made.

Quality Control unit

The quality unit is responsible for activities including approval or rejection of components, containers, closures, packaging and labeling materials, raw materials, in-process materials, and finished drug products.

Quality unit head count

A company's existing head count is not a drug product or material that must be approved and released by the quality control unit.

Sterile manufacturing contamination

Humans are considered the greatest source of product contamination in a sterile drug manufacturing facility.

Sterile manufacturing PPE

Gloves, full-body gowns, shoe covers or booties, and hair covers are used to protect products from contamination.

Steel-toed boots

Not typical PPE used by biotech manufacturing personnel specifically to protect sterile products from human contamination.

21 CFR Part 211 Subpart B

Concerns organization and personnel.

Personnel education and training

Personnel must have appropriate education, cGMP training, and experience to perform assigned functions.

Personnel sanitation

Personnel must observe good sanitation and health habits.

Personnel apparel

Personnel should wear appropriate apparel to protect drug products from contamination.

Controlled personnel access

Certain limited-access manufacturing areas must have controlled personnel access.

HVAC and Subpart B

Appropriate HVAC is a facilities requirement rather than a personnel requirement under Subpart B.

Buildings and facilities cGMP

Facilities must be appropriately designed, sized, maintained, cleaned, and organized to prevent contamination and mix-ups.

Facility size

Facilities must have sufficient space to allow appropriate separation of manufacturing activities.

Facility cleaning

Cleaning should be performed according to written procedures and established schedules.

Facility separation

Facilities should have appropriate divisions or separation between processes to prevent contamination and mix-ups.

Product flow

Facilities should support logical product flow from raw-material receiving through manufacturing and distribution.

Washing and toilet facilities

Facilities must provide appropriate washing and toilet facilities; they do not have to be extremely far from manufacturing suites.

Manufacturing equipment design

Equipment must be appropriately designed and sized for its intended use.

Equipment materials

Equipment should be made from materials that are not highly reactive with the drug product and will not adversely affect product quality.

Equipment cleaning

Equipment must be cleaned and maintained according to written procedures and schedules.

Equipment lubricants

Only appropriate food-grade lubricants or oils should be used where necessary to prevent contamination of drug products.

Equipment replacement parts

The effect of a replacement part on product quality should be evaluated before implementation.

Computerized systems

Computer systems used in manufacturing require controls that ensure consistent operation and protect data integrity.

Computer passwords

Users should have authorized individual access; personnel should not share passwords so others can operate systems in their absence.

Computer backups

Manufacturing computer systems should have appropriate backup procedures to protect data in case of system malfunction.

Software requalification

Significant software changes may require equipment or system requalification to ensure continued proper operation.

Double-checking operations

Important operations may be performed by one person and independently checked by a second person to improve accuracy and reliability.

Validation

Documented evidence providing a high degree of assurance that a specific process, facility, or support system will consistently produce a product meeting predetermined specifications and quality attributes.

Acceptance criteria

Predetermined requirements that a material, process, or product must meet to be accepted.

Calibration

Comparison and adjustment of an instrument against a known standard to ensure accurate measurement.

Change control

Formal process for evaluating, approving, documenting, and implementing changes while assessing their effects on product quality.

CAPA

Corrective and Preventive Action; a quality-system process used to correct problems and prevent their recurrence.

Biotech protein production

The major stages described include cultivation of cells, expansion in larger bioreactors, purification, and filling/formulation of the purified product.

Cell cultivation

Frozen animal cells can be transferred and cultivated in nutrient solution as part of biotherapeutic protein production.

Stainless-steel bioreactors

Cells are transferred into progressively larger stainless-steel bioreactors where they grow and product synthesis occurs.

Chromatography

A purification technique used to isolate the desired biotherapeutic protein from other materials.

Final filling

Purified product is filled into appropriate containers or cryovessels for formulation into the finished drug.

Recombinant DNA in E. coli

Transformation of a recombinant DNA construct into E. coli was not one of the four major phases described in the Roche biotherapeutic production video.

Components, containers, and closures

Materials used in manufacturing, packaging, or holding drug products that must be controlled to prevent contamination, deterioration, and mix-ups.

Receipt of components

Components, containers, and closures should be inspected for correct labels and contents, damage, broken seals, and contamination when received.

Storage of components

Components, containers, and closures should be appropriately stored, including off the floor when required, to prevent contamination and deterioration.

Quarantine

Received components, containers, and closures are quarantined until appropriate sampling, testing, and release requirements are satisfied.

Component approval

Components must meet established specifications and be approved before use in manufacturing.

Container and closure purpose

Containers and closures should protect drug products from contamination and preserve product quality.

Good container/closure property

Containers and closures should not allow contaminants from outside to enter the drug product.

Bad container/closure properties

Containers and closures should not be highly reactive, leach chemicals, allow drug loss, or facilitate moisture entry.

Dispensed component label

May include the component name, weight, intended product batch, and identification/signatures of personnel who weighed and checked the material.

Weighing apparatus manufacturer

The maker of the weighing apparatus is not a required item on a dispensed component container label.

Sampling procedures

Sampling of components, containers, and closures must follow a written, predetermined protocol.

Representative sampling

Samples should be taken from representative/random locations such as the beginning, middle, and end of material when appropriate.

Sampling contamination

Sampling should minimize exposure of materials to air and other contamination sources.

Component testing

Appropriate testing must demonstrate conformity to specifications and identity/quality as required.

Sample labels

Samples should be labeled, dated, and associated with the personnel who performed the sampling.

Acceptance/rejection criteria

Predetermined criteria should establish whether materials are accepted or rejected.

Content uniformity

Measures variability in the amount of API from one dosage unit to another, such as tablet-to-tablet variability.

Content uniformity vs tablet count

Content uniformity does not measure the number of tablets in a container.

Content uniformity vs initial mixing

Content uniformity evaluates dosage-unit variability rather than simply the amount of API added during initial mixing.

Content uniformity vs dissolution

Content uniformity measures the amount of API in dosage units; dissolution measures drug release into a medium over time.

Bioburden

The microbial count or microbial contamination present on or in materials such as raw materials, excipients, and APIs.

Production time limits

Time limitations are established because prolonged or insufficient processing can adversely affect product quality.

Prolonged raw-material holding

Can increase the risk of microbial contamination.

Insufficient mixing

Can cause failed content uniformity in tablets.

Insufficient drying

Can result in unacceptable moisture levels in tablets.

Prolonged drying

Can cause degradation of an API.

Process delay

Delaying market release alone is not primarily a cGMP product-quality reason for establishing a process time limit.

Expiration date

The date on the drug label is based on stability testing and can be affected by storage conditions, especially humidity and temperature.

Laboratory controls

Require that analytical methods for raw materials, in-process materials, and drug products have established and documented accuracy, sensitivity, specificity, and reproducibility.

Accuracy

The ability of a test method to produce results close to the true or accepted value.

Precision

The degree to which repeated measurements agree with one another.

Sensitivity

The ability of a test method to detect an analyte or impurity when present at low levels.