FDA's Guidelines

for GMP of API

W I T H D A LT O N
Peter Pekos

[COMPANY VISION]
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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]
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Development
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 ABOUT

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, Regulation, Gudielines

Act

An Act is a means by which laws

are made that: Regulations
Provide clarity on the definition
and interpretation of the legal Regulations are the operational
framework part of the law, that interprets
Establish actions that are what is meant by the terms,
prohibited provisions, procedures, and
Establish actions that are processes in the Act in order to
permitted comply with the Act
Set out a framework for a
regulatory scheme Regulations are often referred
to as delegated legislation or
subordinate legislation

Regulations should follow and

be consistent with the authority
Guidelines
of the Act which they reflect
Guidance documents provide (Enabling Act)
assistance on how to comply with
laws and regulations. They serve
as an administrative instrument
and are not enforced by law

APIs are subject to the adulteration provisions of 21 USC 501(a)(2)(B), which

requires all drugs to be manufactured in conformance with cGMP.
 ABOUT

API & GMP

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

L-Phenylalanine, Ring-13C6 L-Phenylalanine, 1-13C

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.

Current Good Manufacturing Practices (cGMP)

refers to the continuously evolving GMPs of
drug development. Dalton’s 15 years of
expertise in complex cGMP APIs can support
your clinical development through to
commercialization.
 ABOUT
Quality by Design

"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).

QbD involves having an understanding of:

The product
The process by which it is developed and manufactured along with
The risks involved with manufacturing
How to best mitigate those risks

Risk management involves establishing a risk management framework by

defining the process, roles, and responsibilities and creating a risk management
plan.

Risk Management Plan

Do the
benefits
Are the risks outweigh the
acceptable? risks?

Risk Review and

Risk Control
Analysis Report

Risk Risk
Evaluation Acceptability

Identify hazards Risk

and estimate reduction?
the risk severity

Refer to ICHQ9 for more information on quality risk management.

 ABOUT

Regulations

eCFR Title 21, Part 210-211

The FDA has not implemented regulations specifically for cGMP of APIs. However,
Title 21, Parts 210 - 211 apply to APIs.

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:

Organization and Laboratory Holding and

Personnel Controls Distribution

Responsibilities of Testing and release Warehousing

quality control unit for distribution procedures
Personnel Stability testing Distribution
qualifications Special testing procedures
Personnel requirements
responsibilities Reserve samples
Consultants Laboratory animals
Penicillin
contamination

Buildings and Equipment Packaging and

Facilities Labeling Control

Design and Equipment design, Materials examination

construction features size, and location and usage criteria
Lighting Equipment Labeling issuance
Ventilation, air construction Packaging and
filtration, air heating Equipment cleaning labeling operations
and cooling and maintenance Tamper-evident
Plumbing Automatic, packaging
Sewage and refuse mechanical, and requirements for over
Washing and toilet electronic equipment the counter (OTC)
facilities Filter human drug products
Sanitation Drug product
Maintenance inspection
Expiration dating
 ABOUT

Regulations

Control of Production and Records and

Components and Process Controls Reports
Drug Product
Containers and
Closures
Receipt and storage Written procedures; Equipment cleaning
of untested deviations and use log
components, drug Charge-in of Component, drug
product containers, components product container,
and closures Calculation of yield- closure, and labeling
Testing and approval Equipment records
or rejection of identification Master production
components, drug Sampling and testing and control records
product containers, of in-process Batch production and
and closures materials and drug control records
Use of approved products Production record
components, drug Time limitations on review
product containers, production Laboratory records
and closures Control of Distribution records
Retesting of approved microbiological Complaint files
components, drug contamination
product containers, Reprocessing
and closures
Rejected components,
drug product
containers, and Returned and Salvaged Drug Products
closures Returned drug products
Drug product Drug product salvaging
containers and
closures
 ABOUT

Guidelines

Q GMP for API Guideline

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.

The stringency of GMPs in API manufacturing gradually increases as it gets closer

to the final steps.

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

Buildings and Facilities

- Design and Construction
Must be designed and constructed to facilitate cleaning, maintenance, and
operations and it must be located in a space that permits orderly placement of
equipment and material
Have defined areas for the following:
Receipt, identification, sampling, and quarantine of incoming materials,
Sampling,
Holding,
Storage of released materials,
Production operations,
Packaging and labeling operations, and
Laboratory operations
Toilet facilities should be equipped with hot and cold water
- Utilities - Must have adequate ventilation, air filtration, and exhaust systems
- Water
Water used in the manufacture of an API should be demonstrated to be suitable for
its intended use
Water treatments must be validated and monitored with appropriate action limits
- Containment - Employ dedicated production areas for highly sensitizing materials
(e.g., materials such as penicillins and cephalosporins)
- Lighting - Must have adequate lighting
- Sewage and Refuse - Must be disposed of in a safe, timely, and sanitary manner
- Sanitation and Maintenance

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

Documentation and Records

- Documentation System and Specifications
Prepare, review, approve, and distribute API manufacturing documents per written
procedures
Retain all production, control, and distribution records for at least 1 year after the
complete distribution of the entire batch of the API by the API manufacturer to the
next party in the supply chain. The records should be in their original form. For
APIs with a retest date, retain records for at least 3 years after the batch is
completely distributed.
Records must provide the name of the personnel that entered any information
- Equipment Cleaning and Use Record - Record the date, time, product, and batch
number of cleaning, sanitization, sterilization, and maintenance of all major
equipment’s
- Records of Raw Materials, Intermediates, API Labeling, and Packaging Materials -
Records should include
The name of the manufacturer, identity and quantity of each shipment of each
batch of raw materials, intermediates or labeling and packaging materials for
API's; the name of the supplier; the supplier's control number(s); the number
allocated on receipt; and the date of receipt
Results on tests
- Master Production Instructions (Master Production and Control Records)
Prepare a master production instruction for the API. This should include the API
name, the identifying document reference code, a list of raw materials with their
quality characteristics and quantity, the production location, production
equipment, production instruction, and API storage. This should be reviewed,
dated, and signed by the QA Unit.
- Batch Production Records (Batch Production and Control Records) - Prepare records
for API batch production that includes the:
Date and time,
Major equipment used,
Batch description (e.g., number, weight),
Sampling performed,
Laboratory test results,
Packaging and labeling information, and
Deviations and evaluations
- Laboratory Control Records
Record a description of samples received for testing. This description
should include material name, batch number, and quantity
Date the sample was received for testing and date it was sampled
Reference to each test method
Weight of sample used for each test
Record of all raw data
Signature of the personnel who performed each test and of the personnel who
reviewed it
- Batch Production Record Review - Establish written procedures for the review and
approval of batches
 ABOUT

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

Production and Inprocess Controls

- Production Operations
Weigh or measure API in a way that does not affect its suitability for use. Activities
should be witnessed or subjected to an equivalent control
Compare actual yields with expected yields. Explain and document any deviations;
investigate if necessary
- Time Limits - Meet the time limits in the master production instruction
- In-process Sampling and Controls - Establish written procedures
- Blending Batches of Intermediates or APIs
Do not blend out-of-specification batches with other batches
Acceptable blending operations:
Blending of small batches to increase the batch size
Blending tailings from batches of the same API to form a single batch
Control, test, and document any blending processes
- Contamination Control - If there is adequate control, residual materials can be
carried over into successive batches of the same API
 ABOUT

Guidelines

Packaging and Identif ication Labeling of API

- General
Establish written procedures for the receipt, identification, quarantine, sampling,
examination/testing, release, and handling of packaging and labeling materials
Maintain records for each shipment of labels and packaging materials showing the
receipt, examination, or testing, and an indication on whether it was accepted or
rejected
- Packaging Materials - Packaging material containers should provide adequate
protection against deterioration or contamination
- Label Issuance and Control
Limit access to authorized personnel
Destroy out-dated labels
- Packaging and Labeling Operations

Storage and Distribution

- Warehousing Procedures - Facilities should have available storage area with
conditions that can be altered (e.g., controlled temperature and humidity when
necessary)
- Distribution Procedures
Release APIs for distribution to third parties only if it has been released by the
quality unit
Transportation of APIs must not affect its quality

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

Complaints and Recalls

- Manufacturers, importers and distributors are obligated to maintain records of
reported problems and all actions taken in response to these problems
- Manufacturers, importers and distributors are also obligated to establish and
implement documented procedures for effective and timely investigation/ response
Complaint handling procedure: Identify activities that must take place, identify
personnel involved and their role, identify how to maintain and access records,
identify timeframes for completion of investigations
Failure to do so results in penalties, including imprisonment
- Record and investigate the following information
Name and address of the complainant
Name and phone number of the person submitting the complaint
Complaint nature (including name and batch number of the API)
Awareness Date
CAPA
Response provided to the originator of complaint (including date the response
was sent)
Decision on API batch or lot
- Adverse drug reaction report
MedWatch (FDA 3500a) for adverse drug reactions in the US
CIOMS for adverse drug reactions outside the US
 ABOUT

Guidelines

Rejection and Reuse of Materials

- Rejection and Reuse of Materials
Rejection Recovery of materials and solvents
Reprocessing Returns
Reworking

APIs for Use in Clinical Trials

- Quality
Apply GMPs
Establish quality unit(s) independent, from production, for the approval or rejection
of each batch of API
- Equipment and Facilities
During all phases, equipment should be calibrated, clean, and suitable
It is permitted to use the same equipment to manufacture materials in both
preclinical and clinical trials
- Control of Raw Materials - Evaluate by testing
- Production
Document in lab notebooks or batch records
Expected yields can be more variable and less defined than the expected yields
used in commercial processes
- Validation - Only necessary for batches that are produced for commercial use
- Changes - Record all changes
- Laboratory Controls
Have a system for retaining reserve samples of all batches
The same expiry and retest dating requirement for non-clinical APIs applies to
existing clinical APIs. However, this does not apply to new clinical APIs in the early
clinical stages
- Documentation - Implement a system to document analytical methods, production,
and control records
 ABOUT

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.

We pay special attention to equipment

qualification and process validation and
provide full regulatory support for our
clients. Dalton can develop, create, and
execute validation protocols and studies
required for your products and equipment
in accordance with current regulations
and guidelines (U.S. FDA, Health Canada,
EMA, ICH, and WHO) and acceptable
formats (prospective, retrospective, and
concurrent).

Learn more about our API Manufacturing capabilities here.

 REFERENCES

1. FDA. (2016). Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical

Ingredients Guidance for Industry. Food and Drug Administration.
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q7-good-
manufacturing-practice-guidance-active-pharmaceutical-ingredients-guidance-
industry
2. FDA. (2018). Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients Questions and Answers Guidance for Industry. Food and Drug
Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/q7-good-manufacturing-practice-guidance-active-pharmaceutical-
ingredients-questions-and-answers
3. FDA. (2019). Questions and Answers on Current Good Manufacturing Practices—
Production and Process Control. Food and Drug Administration.
https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-
manufacturing-practices-production-and-process-controls

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

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Peter Pekos