FDA GMP Guidlines For API Whitepaper
FDA GMP Guidlines For API Whitepaper
[COMPANY VISION]
"To make the impossible possible. Dalton Pharma Services uses its scientific
and pharmaceutical expertise to bring customer ideas to life. We develop their
new drug products, optimize the synthesis of therapeutic candidates, and
manufacture them at the highest level of quality."
[SERVICES]
Contract Research
Custom Synthesis
Medicinal and Flow Chemistry
API Process Development Formulation
Development
cGMP API Manufacturing
cGMP Sterile Filling
Analytical and Microbiology Services
Legislative Framework
Disclaimer
This technical report is intended to provide information to quality and regulatory
correspondents on FDA’s guidelines for the good manufacturing practices of active
pharmaceutical ingredients. This technical report should be read in conjunction with the
relevant laws, regulations, and guidance's that apply to your situation.
Act
GMP
API
An active pharmaceutical ingredient is defined as a
“(A) substance, or a mixture when the substance is unstable or cannot be transported
on its own, intended
(i) to be used as a component of a drug; and
(ii) to furnish pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease, or to affect the structure or any
function of the human body; or
(B) substance intended for final crystallization, purification, or salt formation, or any
combination of those activities, to become a substance or mixture described in
subparagraph (A)” (FDA, 2016).
Once the API form is determined, the dosage form must be selected. To learn more about
dosage form development refer to Dalton’s API and dosage form development technical
report.
The quality of the API in a drug has a direct effect on the safety and efficacy of that drug.
Therefore, GMP is a critical part of API development.
DOPC
GMP
Good Manufacturing Practices (GMP) is a
system for ensuring that products are
consistently produced and controlled
according to quality standards, as required by
the market authorization license.
Therefore, GMP serves to protect the health of
the public.
"Quality After Design" involves increased testing after product production. This
approach was the mainstay by drug manufacturing companies up until the
1990s. In the 1990s FDA recognized that increased testing does not necessarily
improve product quality but rather building quality into a product does.
The notion of building quality into a product to improve product quality became
known as Quality by Design (QbD).
Risk Risk
Evaluation Acceptability
Regulations
Part 210 states that the cGMPs outlined in part 211 are appliable to the
manufacture, processing, packing, or holding of a drug. Note: The production of
an investigational drug for use in a phase 1 study is exempt from compliance with
the regulations in part 211. The cGMP requirements outlined in Part 211 are:
Regulations
Guidelines
The guidance document “Q7 Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients Guidance for Industry” represents FDA’s current
thinking of GMPs for the production, packaging, repackaging, labeling, relabeling,
quality control, release, storage, and distribution of APIs and replaces the
guidance document “Q7A Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients.”
Out of scope: vaccines, whole cells, whole blood and plasma, blood and plasma
derivatives (plasma fractionation), gene therapy, medical gases, bulk-packaged
drug (medicinal) products (e.g., tablets or capsules in bulk containers), and
radiopharmaceuticals APIs.
Quality Management
- The Quality Control Unit is responsible for
All activities (e.g., tests) and decisions concerning the quality of the product
Releasing or rejecting APIs
Establishing a system to release or reject raw materials, intermediates, packaging,
and labeling materials
The Quality Assurance Unit is responsible for
- Reviewing and approving all quality-related documents
Ensuring compliance to GMPs
Ensuring self-inspection audits are performed
Analyzing quality non-conformance issues and suggesting corrective and
preventive actions (CAPA)
- Internal audits - Ensure investigation and CAPA for critical deviations and complaints
- Product quality review - A product quality review that includes trend analysis is
expected annually
Personnel
- Personnel qualifications - Personnel must have education, training that is periodically
assessed, and experience
- Personal hygiene - Personnel should avoid direct contact with APIs
- Consultants - If a consultant is used, they must be qualified by education, regular
training, and experience
ABOUT
Guidelines
Process Equipment
- Design and construction
Must have an appropriate design and adequate size. Locate in a space that
permits for its intended use, cleaning, sanitization, and maintenance
Only use production equipment in its qualified operating range
Equipment processing aids should not contact APIs
- Equipment Maintenance & Cleaning
Establish schedules and procedures for the preventative maintenance of equipment
Inspect equipment for cleanliness before use
Establish schedules and procedures for the cleaning of equipment
Keep a record of the methods and materials used to clean equipment
- Calibration
Establish a schedule and written procedures for the calibration of equipment used
to control, weigh, measure, monitor, and test APIs. Base calibrations on certified
standards and document this
Do not use equipment that does not meet calibration acceptance standards
- Computerized Systems
Validate GMP related computerized systems
Have sufficient controls to prevent unauthorized access and to verify the input of
critical data
Establish written procedures for its operation
Have a backup system
ABOUT
Guidelines
Guidelines
Material Management
- General Controls - Establish written procedures for the receipt, identification,
quarantine, storage, handling, sampling, testing, approval or rejection, and supplier
evaluation of materials
- Receipt and Quarantine
Visually examine each container of materials upon receipt and before acceptance
Quarantine material until sampling, examination, or testing, has been conducted
- Sampling and Testing of Incoming Production Materials
Test incoming material to verify the identity of each batch
A supplier's certificate of analysis can be used in place of performing a test
- Storage - Store and handle material in a way that prevents degradation,
contamination, and adverse effect on its quality
- Re-evaluation - Re-evaluate materials to determine if they are still suitable for use
(e.g., after prolonged storage or exposure to heat or humidity)
Re-evaluate
Sample
Quarantine
Store
Guidelines
Laboratory Controls
- Testing of Intermediates and APIs - Establish an impurity profile for a typical batch
produced by a specific controlled production process
- Validation of Analytical Procedures
- Certificates of Analysis - Authentic Certificates of Analysis should be issued for each
API batch on request
- Stability Monitoring of API - An ongoing testing program should be designed to
monitor the stability characteristics of an API, and the results should be used to
confirm appropriate storage conditions and retest or expiry dates
- Expiry and Retest Dating
An API expiry or retest date should be based on an evaluation of data derived from
stability studies. Common practice is to use a retest date, not an expiration date
The retest date can be extended based on good science and long-term stability
results and if the batch has been stored correctly
- Reserve/Retention Samples - Retain API batch samples in the case of future quality
evaluation. Serves as a legal basis since retention samples permit for a thorough and
effective investigation for complaint handling
ABOUT
Dalton's
Guidelines
Services
Validation
- Validation Policy - Document the company's overall policy, intentions, approach to
validation, validation of production processes, cleaning procedures, analytical
methods, in-process control test procedures, computerized systems, and persons
responsible for design, review, approval, and documentation of each validation phase.
- Qualification - Document verification of Design Qualification (DQ), Installation
Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ)
- Process Validation
Types of process validation
1) Prospective validation: Perform for all API processes before the commercial
distribution of the final drug product manufactured from that API
2) Concurrent Validation: A subset of prospective validation that is conducted to
ultimately distribute product manufactured during the validation study and
which becomes the In Process Quality Control Tests (I.P.Q.C) tests
3) Retrospective Validation: Confirms the impurity specifications for each API
- Periodic Review of Validated Systems
- Cleaning Validation - Validations should reflect the actual process carried out during
equipment cleaning
- Validation of Analytical Methods - Methods should be validated to include
consideration of characteristics included within the ICH guidelines on validation of
analytical methods. The degree of analytical validation performed should reflect the
purpose of the analysis and the stage of the API production process
Guidelines
Dalton's Services
GMP
cGMP API Manufacturing
Dalton is a leader in the development and
manufacture of complex cGMP Active
6-Gingerol
Pharmaceutical Ingredients (APIs). Our
expert scientists, coupled with newly
updated and renovated cGMP development
and manufacturing facility allow us to
Myristyl gamma-
support API Synthesis. We conduct cGMP
manufacturing of APIs for all stages of pre- picolinium chloride
clinical and clinical trials, from grams to
multi-kilos.
4. FDA. (2004). CPG Sec. 490.100 Process Validation Requirements for Drug Products
and Active Pharmaceutical Ingredients Subject to Pre-Market Approval. Food and Drug
Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/cpg-sec-490100-process-validation-requirements-drug-products-and-
active-pharmaceutical-ingredients
Connect with Us
Call Us
(416)-661-2102
(800)-567-5060
Write Us
Dalton Pharma Services
349 Wildcat Rd.
Toronto, ON M J S
#DaltonPharmaServices
Email Us
[email protected] https://www.dalton.com
Peter Pekos