Contract
Manufacturing
Arrangements for Drugs:
Quality Agreements
Guidance for Industry
U.S. Department of
Health and Human Services Food and Drug Administration
Center for Drug
Evaluation and Research (CDER) Center for Biologics Evaluation and Research
(CBER) Center for Veterinary Medicine (CVM)
November 2016
Pharmaceutical
Quality/Manufacturing Standards (CGMP)
Additional copies are
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Food and Drug
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Email: druginfo@fda.hhs.gov http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
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and/or
Policy and
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Administration
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U.S. Department of
Health and Human Services Food and Drug Administration
Center for Drug
Evaluation and Research (CDER) Center for Biologics Evaluation and Research
(CBER) Center for Veterinary Medicine (CVM)
November 2016
Pharmaceutical
Quality/Manufacturing Standards (CGMP)
I. INTRODUCTION
II. DEFINING THE WHO AND WHAT
OF CONTRACT MANUFACTURING
III. RESPONSIBILITIES OF PARTIES
INVOLVED IN CONTRACT MANUFACTURING
IV. DOCUMENTING CGMP ACTIVITIES
IN QUALITY AGREEMENTS
A. What Is a Quality Agreement?
B. Elements of a Quality
Agreement
1. Manufacturing Activities
2. Change Control Associated With
Manufacturing Activities
V. ILLUSTRATIVE SCENARIOS
A. Owners and Contract
Facilities Are Both Responsible for CGMP
B. CGMPs Apply to all Contract
Facilities, Including Analytical Testing Laboratories
C. Owners and Contract
Facilities Perform Change Control Activities
VI. RECOMMENDATIONS
Contract Manufacturing Arrangements for Drugs:
Quality Agreements
This guidance represents the current thinking of
the Food and Drug Administration (FDA or Agency) on this topic. It does not
establish any rights for any person and is not binding on FDA or the public.
You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach,
contact the FDA office responsible for this guidance as listed on the title
page.
I.
INTRODUCTION
This guidance
describes FDA’s current thinking on defining, establishing, and documenting
manufacturing activities of the parties involved in contract drug manufacturing
subject to current good manufacturing practice (CGMP) requirements. In particular,
we describe how parties involved in contract drug manufacturing can use quality
agreements to delineate their manufacturing activities to ensure compliance
with CGMP.
For purposes
of this guidance, we use certain terms with the following specific meanings:
·
Current Good Manufacturing
Practice (CGMP) refers to requirements in the Federal Food, Drug, and Cosmetic Act
(FD&C Act), section 501(a)(2)(B), for all drugs and active pharmaceutical
ingredients (APIs). For finished human and animal drugs, the term includes applicable requirements
under 21 CFR parts 210 and 211. For biologics, the term includes additional
applicable requirements under 21 CFR parts 600-680.
·
Commercial
manufacturing refers to manufacturing processes that result in a drug or drugs intended to be marketed,
distributed, or sold.
·
Commercial manufacturing does not include research
and development activities, manufacturing of material for investigational new
drug studies (e.g., clinical trials, expanded access), or manufacturing of
material for veterinary investigational drugs. Although this guidance does not
explicitly apply to the manufacture of investigational, developmental, or
clinical trial materials, FDA believes that quality agreements can be extremely
valuable in delineating the activities of all parties involved in contract research
and development arrangements. Many of the principles described in this guidance
could be applied in pre-commercial stages of the pharmaceutical life cycle.
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1 This guidance has been
prepared by the Office of Pharmaceutical Quality and the Office of Compliance
in the Center for Drug Evaluation and Research in cooperation with the Center
for Biologics Evaluation and Research, the Center for Veterinary Medicine, and
the Office of Regulatory Affairs at the Food and Drug Administration.
·
Manufacturing
includes processing, packing, holding, labeling operations, testing, and quality unit operations.
·
A manufacturer is
an entity that engages in CGMP activities, including implementation of oversight and controls over the manufacture
of drugs to ensure quality.2
This guidance
covers commercial manufacturing of the following categories of drugs: human
drugs, veterinary drugs, certain combination products, biological and
biotechnology products, finished products, APIs, drug substances, in-process
materials, and drug constituents of combination drug/device products.4 This guidance does not cover the
following types of products: Type A medicated articles and medicated feed,
medical devices, dietary supplements, or human cells, tissues, or cellular or
tissue-based products regulated solely under section 361 of the Public Health
Service Act and 21 CFR part 1271.
In general,
FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory
requirements are cited. The use of the word should
in Agency guidances means that something is suggested or recommended, but
not required.
II.
DEFINING
THE WHO AND WHAT OF CONTRACT MANUFACTURING
This guidance
describes how contract manufacturing operations fit within the larger scheme of
pharmaceutical quality systems. It also presents the Agency’s current thinking
on the roles and manufacturing activities of the parties involved in contract
manufacturing arrangements.
Specifically,
this guidance addresses the relationship between owners and contract
facilities. For purposes of this guidance, we define owners as manufacturers of APIs, drug substances, in- process
materials, finished drug products, including biological products, and
combination products. The term owner does
not apply to retail pharmacies, drug stores, supermarkets, discount warehouse
stores, or other retailers who purchase finished drug products to sell over the
counter as a store brand. For purposes of this guidance, we define contract facilities as parties that
perform one or more manufacturing operations on behalf of an owner or owners.5
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2 See section
501 of the FD&C Act, as amended by the Food and Drug Administration Safety
and Innovation Act (Public Law 112-144, title VII, section 711).
4 Combination product manufacturers can apply this guidance to their
quality agreements because they are subject to requirements under 21 CFR part
211 and/or 21 CFR part 820 (see 21 CFR 4.3). In addition to facilitating
compliance with requirements under 21 CFR part 211, manufacturers can use
quality agreements with contract facilities to demonstrate compliance, in part,
with 21 CFR 820.50 (purchasing controls) and with 21 CFR 820.80(b) (receiving
acceptance activities) for combination products.
5 A contract facility may also be an owner depending on its role (e.g.,
when the contract facility is using a
subcontractor).
Drug
manufacturing encompasses many discrete operations and activities. One
manufacturer may perform all operations and activities or may engage an outside
party or parties to perform some or all of the operations and activities under
contract. Contract facilities perform a variety of manufacturing operations and
activities, including but not limited to:
·
Formulation
·
Fill and finish
·
Chemical synthesis
·
Cell culture and fermentation, including for biological products
·
Analytical testing and other laboratory services
·
Packaging and labeling
·
Sterilization or terminal sterilization
However,
agreements between owners and contract facilities sometimes do not clearly
define the CGMP-related roles and manufacturing operations and activities of
each of the parties. When all parties clearly understand their CGMP-related
roles and manufacturing responsibilities, the owners who use contract
facilities, contract facilities that provide services to owners, and,
ultimately, patients who take the drugs manufactured under these arrangements
may benefit in many ways. Contracting can enhance speed and efficiency, provide
technological expertise, and expand capacity.
We encourage
entities that engage in manufacturing related solely to drug distribution
(e.g., distributors, brokers, private label distributors, own label
distributors) to follow the recommendations in this guidance document, as
appropriate. Our focus here, however, is on the roles and manufacturing
activities of the owner and contract facility.
III.
RESPONSIBILITIES
OF PARTIES INVOLVED IN CONTRACT
MANUFACTURING
Each party
engaged in the manufacture of a drug is responsible for ensuring compliance
with CGMP for the manufacturing activities it performs.6
For both owners and contract facilities that conduct manufacturing operations,
CGMP “includes the implementation of oversight and controls over the
manufacture of drugs to ensure quality, including managing the risk of and
establishing the safety of raw materials, materials used in the manufacturing
of drugs, and finished drug products.”7
Drugs not manufactured in compliance with CGMP are adulterated.8
The FD&C
Act also prohibits any person from introducing or delivering for introduction
an adulterated or misbranded drug into interstate commerce.9
In addition, it prohibits anyone from the “doing of any … act with respect to,
a … drug … if such act is done while such article is held
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for sale …
after shipment in interstate commerce and results in such article being
adulterated or misbranded.”10
FDA’s
regulations recognize that owners commonly use contract facilities to perform
some drug manufacturing activities.11
When an owner uses a contract facility, the owner’s quality unit is legally
responsible for approving or rejecting drug products manufactured by the
contract facility, including for final release.12
The regulations require that the quality unit’s responsibilities and procedures
be in writing and that they be followed.13
Owners can
use a comprehensive quality systems model to help ensure compliance with CGMP.
A comprehensive quality systems model anticipates that many owners will use
contract facilities and calls for quality agreements between owners and
contract facilities. Quality agreements should clearly describe the materials
or services to be provided, quality specifications, and communication
mechanisms between the owner and contract facility. See guidance for industry Quality Systems Approach to Pharmaceutical
CGMP Regulations.14
Owners and
contract facilities can review FDA guidance documents for recommendations on
achieving compliance with CGMP. Various FDA guidance documents describe how
quality management principles relate to contract manufacturing operations,
including some of the roles and manufacturing activities of contract
manufacturing parties.15
The following
three ICH guidances for industry contain relevant and valuable CGMP
recommendations with respect to contract manufacturing arrangements:
·
Q7 Good Manufacturing
Practice Guidance for Active Pharmaceutical Ingredients
·
Q9 Quality Risk Management
·
Q10 Pharmaceutical Quality System
ICH guidance
for industry Q7 Good Manufacturing
Practice Guidance for Active Pharmaceutical Ingredients recommends that
owners evaluate contract facilities to ensure that contractor sites comply with
CGMP for specific operations.16
It also recommends that owners have approved written agreements with
contractors that define the manufacturing responsibilities in detail, including
the quality measures, of each party. The written agreements should also define
considerations for subcontracting; describe how changes to processes,
equipment, methods, and specifications will be managed; and permit the owner to
audit its contractor’s facilities for compliance with CGMP.
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14 We update guidances periodically. To make sure you have the most recent
version of a guidance, check the FDA Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
ICH guidance
for industry Q9 Quality Risk Management offers
a systematic approach to quality risk management as part of an effective
quality system. It discusses quality risk management principles such as risk
assessment, risk communication, and risk review and provides examples of tools
that can be used to make effective and efficient risk-based decisions in, for
example, auditing and arranging quality agreements with contract manufacturers.
ICH guidance
for industry Q10 Pharmaceutical Quality
System states that, as part of a pharmaceutical quality system, the owner
is ultimately responsible for ensuring that “processes are in place to assure
the control of outsourced activities and quality of purchased materials.”17 It indicates that these processes
should incorporate quality risk management and include the following critical
activities:
·
Assessing the suitability and competence of potential
contractors before outsourcing operations or selecting material suppliers. This
could be accomplished through audits,
material evaluations, or other qualification
criteria.
·
Defining the manufacturing responsibilities and
communication processes for quality- related activities of the involved
parties. For outsourced activities, these should be in a written agreement.
·
Monitoring and reviewing the performance of the
contract facility and identifying and
implementing any needed improvements.
·
Monitoring incoming ingredients and materials to ensure they are from
approved sources using the
agreed-upon supply chain.
FDA
encourages parties engaged in contract manufacturing to implement quality
management practices. This guidance is intended to build upon the quality risk
management principles and recommendations outlined above and to illustrate key
points in developing and executing quality agreements that describe and support
contract manufacturing arrangements.
IV.
DOCUMENTING
CGMP ACTIVITIES IN QUALITY AGREEMENTS
If an owner
employs a contract facility for all or part of the manufacturing (including
processing, packing, holding, or testing) of a drug or drug product, the
owner’s quality unit is responsible for approving or rejecting the contract
facility’s product or service.18
The contract facility is also required to comply with statutory CGMP and
applicable CGMP regulations, including requirements for its quality unit.19 CGMP regulations require that quality
unit activities and procedures be in writing, and that these procedures be
followed.20
Implementing
a written quality agreement can facilitate compliance with CGMP and, in
particular, with 21 CFR 211.22(d), which states that quality unit activities
and procedures should be in writing. FDA recommends that owners and contract
facilities establish a written quality agreement to describe their respective
CGMP-related roles, responsibilities, and activities in drug
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manufacturing.
It is important to note that quality agreements cannot be used to delegate
statutory or regulatory responsibilities to comply with CGMP. The following
sections describe the Agency’s current thinking regarding the documentation of
agreed-upon manufacturing activities in a quality agreement, as well as the
basic elements of a quality agreement.
A.
What
Is a Quality Agreement?
A quality
agreement is a comprehensive written agreement between parties involved in the
contract manufacturing of drugs that defines and establishes each party’s
manufacturing activities in terms of how each will comply with CGMP. In
general, the quality agreement should clearly state which party — the owner or
the contract facility or both — carries out specific CGMP activities. It should
cover activities mentioned in section 501(a)(2)(B) of the FD&C Act and, as
applicable, those in 21 CFR parts 210, 211, 600-680, 820, and 1271, as well as
all other applicable statutory or regulatory requirements. Representatives from
each party’s quality unit and other relevant stakeholders should participate
actively in the drafting of quality agreements.
Quality
agreements should not cover general business terms and conditions such as
confidentiality, pricing or cost issues, delivery terms, or limits on liability
or damages. FDA recommends that quality agreements be separate documents, or at
least severable, from commercial contracts such as master services agreements
or supply agreements. Quality agreements may be reviewed during inspections.21
B.
Elements
of a Quality Agreement
A quality
agreement describes the owner’s and the contract facility’s roles and
manufacturing activities under CGMP. A well-written quality agreement will use
clear language. It will define key manufacturing roles and responsibilities. It
will establish expectations for communication, providing key contacts for both
parties. It will specify which products and/or services the owner expects from
the contract facility and who has final approval for various activities. Most
quality agreements contain the following sections:
·
Purpose/Scope — to cover the nature of the contract
manufacturing services to be provided
·
Definitions — to ensure that the owner and contract
facility agree on precise meaning of terms in the quality agreement
·
Resolution of disagreements — to explain how the
parties will resolve disagreements
about product quality issues or other problems
·
Manufacturing activities — to document quality unit and
other activities associated with manufacturing processes as well as control of
changes to manufacturing processes
·
Life cycle of, and revisions to, the quality agreement
The owner may
consider including the contract facility’s established processes and procedures
as part of the quality agreement (for example, by incorporating certain
standard operating
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procedures by
reference). Doing so could reduce the risk of misinterpretation or error during
manufacturing. The quality agreement should explain how the contractor will
report manufacturing deviations to the owner, as well as how deviations will be
investigated, documented, and resolved in compliance with CGMP. Quality
agreements should state that manufacturing services provided by contract
facilities (including laboratories) will comply with CGMP.
From a CGMP
perspective, manufacturing activities are the most important element in a
quality agreement. The most critical pieces are quality and change control, as
described in the following sections.
Quality
agreements may document each party’s roles and manufacturing activities with a
variety of formats — charts, matrices, narratives, or a combination of these.
Regardless of the format, a quality agreement should clearly document which
party is responsible for specific activities. No party to a quality agreement
may delegate any of its responsibilities to comply with CGMP through the
quality agreement or any other means. The quality agreement should cover all of
the activities for ensuring compliance with CGMP. Depending on the scope of the
contract manufacturing services to be provided, the quality agreement should
indicate whether the owner or contract facility (or both) will handle specific
activities related to each of the following topics:
The section of
a quality agreement that addresses each party’s quality unit activities should
define in detail how the parties will work together to ensure that products are
manufactured in compliance with CGMP. Note that assigning quality control or
other activities to either the owner or contract facility in the quality
agreement does not relieve either party from compliance with applicable CGMP
requirements.
In
particular, this section of the quality agreement should be clear with respect
to product release. Contract facilities are responsible for approving or
rejecting the product or results of their manufacturing operations (e.g., test
results, finished dosage forms, or in-process materials).22
In addition, owners are responsible for approving or rejecting drugs
manufactured by the contract facility,23 including
for final release. In all cases, the owner must not introduce or deliver into
interstate commerce, or cause to be introduced or delivered into interstate
commerce, any drugs that are adulterated or misbranded.24
Within its
quality unit activities, a quality agreement should describe how and when the
owner and contract facility will communicate with each other, both verbally and
in writing. This includes identifying appropriate contact personnel within the
owner’s and contract facility’s organization.
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Quality
agreements should also cover audits, inspections, and communication of
findings. The agreement should allow owners to evaluate and audit contract
facilities to ensure CGMP compliance for specific operations. This provision
should cover both routine quality audits and for-cause audits. The agreement
should also set owner and contract facility expectations regarding FDA
inspections (pre-approval, routine surveillance, and for-cause) with consideration for the nature of the
products to be manufactured and/or services to be provided. It should include the parties’ agreed-upon
provisions for communicating inspection observations and findings, as well as
relevant FDA actions and correspondence.
Because
contract facilities often provide services to multiple owners, the quality
agreement should address when, how, and what information the contractor will
report to owners about objectionable
conditions observed during inspections and audits of the contract facility.
This section
of a quality agreement should identify the specific site(s) where the contract
facility will perform manufacturing operations, including the address of and
specific services to be provided at each site. It should indicate which party
will be validating processes and qualifying and maintaining equipment and
applicable systems relevant to the contracted operations. These include
information technology and automated control systems, environmental monitoring
and room classification, utilities, and any other equipment and facilities that
must be maintained to perform the contracted manufacturing operations in
compliance with CGMP. The agreement also should identify which party will
approve equipment validation, qualification, and maintenance activities. In
addition, it should indicate how the parties will communicate information about
preventing cross-contamination and maintaining traceability when a contract
facility processes drugs for multiple owners.
This section
of a quality agreement should indicate which party will establish
specifications for components as well as which party will establish processes
for auditing, qualifying, and monitoring component suppliers. It should also
identify which party will conduct required sampling and testing in compliance
with CGMP. This section of the quality agreement should address how the parties
will ensure appropriate inventory management, including labeling, label
printing, inventory reconciliation, and product status identification (e.g.,
quarantine). The agreement should address how the contract facility will
prevent mix-ups and cross- contamination. FDA does not expect the agreement to
contain a complete description of the supply chain for each component. However,
the agreement should define responsibility for physical control of materials at
different points in the manufacturing process. For example, the quality
agreement should cover responsibilities for proper conditions for storing and
transporting or shipping materials. It should define each party’s roles in
storage and transport — whether from the contract facility back to the owner or
to another contract facility for further operations. This includes defining
activities for monitoring or validating shipping conditions as appropriate.
A
comprehensive quality agreement may address specific considerations related to
individual products. The owner and contract facility might opt to include this
information in an appendix, or directly in the body of the quality agreement.
In either case, if included, this section of the quality agreement should
include the parties’ expectations of each other regarding:
·
Product/component specifications
·
Defined manufacturing operations, including batch numbering processes
·
Responsibilities for expiration/retest dating, storage and shipment,
and lot disposition
·
Responsibilities for process validation, including design,
qualification, and ongoing verification and
monitoring
·
Provisions to allow owner personnel access to the contract facility
when appropriate
The quality
agreement also should indicate how owners will transfer knowledge, such as
product and process development information, to contract facilities to ensure a
drug can be manufactured in compliance with CGMP, and conversely how contract
facilities should share with owners product quality information gained
throughout the product life cycle. This applies to knowledge about all drugs,
including drugs subject to an approved application (e.g., new drug application)
and nonprescription drug products marketed under an over-the-counter drug
monograph.
Owners that
hold an approved drug application should be aware of application and approval
requirements that could affect manufacturing activities. Both parties to a
quality agreement should share relevant information to ensure compliance with
CGMP and other applicable requirements of the FD&C Act.
The owner and
contract facility should both have access to adequate laboratory facilities for
testing of their drugs. A quality agreement will help each party meet this need
by defining roles and
responsibilities for laboratory controls. We recommend the following elements:
·
Procedures delineating controls over sampling and testing samples
·
Protocols and procedures for communicating all
laboratory test results conducted by contract facilities to the owner for
evaluation and consideration in final product disposition decisions
·
Procedures to verify that both owner and contract
facilities accurately transfer development, qualification, and validation
methods when an owner uses a contract
facility for laboratory testing
·
Routine auditing procedures to ensure that a contract
facility’s laboratory equipment is qualified, calibrated, and maintained in a
controlled state in accordance with CGMP
·
Designation of responsibility for investigating
deviations, discrepancies, failures, out-of- specification results,25 and out-of-trend results in
the laboratory, and for sharing reports of such investigations
The quality
agreement should define expectations between the contract facility and the
owner to review and approve documents. It also should describe how changes may
be made to standard operating procedures, manufacturing records,
specifications, laboratory records, validation documentation, investigation
records, annual reports, and other documents related to products or services
provided by the contract facility. The quality agreement should also define
owners’ and contract facilities’ roles in making and maintaining original
documents or true copies in accordance with CGMP. It should explain how those
records will be made readily available for inspection.
The quality agreement also
should indicate that electronic records will be stored in accordance with CGMP
and will be immediately retrievable during the required record-keeping time
frames established in applicable regulations.
Either an
owner or a contract facility may initiate changes to processes, equipment, test
methods, specifications, and other contractual requirements. Both parties
should discuss changes and address them in the quality agreement. There are
some changes that owners should review and approve before they are implemented
and other changes contractors may implement without notifying the owner. How
all changes are managed should be outlined in the agreement, including
allocation of responsibilities for conducting validation activities as needed
before implementing changes. Additionally, both parties should be aware of
those changes that need to be submitted to FDA in a supplement or annual
report. The owner and contract facility should carefully consider and agree on
the types of changes to report to each other and to FDA and the need for
approval from each party’s quality unit and FDA, as applicable. The quality
agreement should address expectations for reporting and approving changes to
the following:
·
Components and/or their suppliers
·
Establishment locations
·
Manufacturing processes
·
Products or product types that use the same production line, equipment
train, or facility
·
Testing procedures
·
Major manufacturing equipment
·
Shipping methods
·
Lot numbering scheme
·
Container closure systems
·
Tamper evidence features
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·
Product distribution
Various
unexpected events, such as manufacturing deviations, complaints, product
recalls, adverse event reports, master label changes, field alert reports, and
biological product deviation reports, may necessitate changes to processes and
procedures. Process improvement projects, process capability analyses, and
trending reports may also necessitate changes to processes and procedures. The
quality agreement should include the owner’s and contract facility’s
expectations for reporting and communication in case of unexpected events and
related changes.
V.
ILLUSTRATIVE SCENARIOS
The following
hypothetical scenarios illustrate common problems in contract manufacturing
arrangements and depict ways in which both owners and contract facilities can
affect product quality. These scenarios also demonstrate FDA’s current thinking
regarding potential ways to resolve problems. The examples provided are not
intended to encompass all drug manufacturing problems related to arrangements
between owners and contract facilities. Rather, they provide industry and other
stakeholders with patterns FDA investigators frequently encounter and analyses
of the facts within these patterns.
A.
Owners
and Contract Facilities Are Both Responsible for CGMP
Case 1: Facilities and Equipment Maintenance and Upkeep at Contract
Facility
An FDA
inspection of a contract facility that manufactures an injectable drug product
for an owner reveals significant objectionable conditions at the contract
facility. Most of the objectionable conditions relate to deficient maintenance
of facilities and equipment used to manufacture the injectable drug product.
Equipment is
broken. Pipes are tarnished, and seals are leaking. In addition, the facility
design does not adequately prevent contamination. A quality agreement between
the contract facility and the owner states that the owner is responsible for
upgrades and maintenance of the facilities and equipment used to manufacture
the owner’s product. The owner has failed to provide upgrades and perform
maintenance, and the contract facility continues to manufacture the product
under non-CGMP conditions with risk of contamination.
Case 2: Documenting Steps in the Manufacturing Process
A contract
facility is manufacturing a prescription drug product for an owner. FDA has
approved an application from the owner for this drug. On inspection, FDA
observes that the contract facility’s batch records do not accurately reflect
the actual manufacturing process because the batch records do not document the
addition of reclaimed powder. Despite the fact that the batch records are
inaccurate and are therefore not compliant with CGMP, the contract facility
claims that its batch records comply with expectations set out in the quality
agreement with the owner.
In the cases
described above, the owners and contract facilities appear to be in violation
of CGMP. A quality agreement cannot exempt owners or contract facilities from
statutory or
regulatory
responsibilities to comply with applicable CGMP, regardless of whether the
quality agreement specifically discusses those CGMP requirements. In case 1,
the contract facility violates CGMP requirements by continuing to manufacture
on outdated or poorly designed equipment, even though the quality agreement
says that the owner is responsible for maintenance and upkeep of the equipment.
In case 2, the contract facility violates CGMP by using a batch record that
does not accurately reflect the manufacturing process, even though the batch
record is consistent with what was set out in the quality agreement.
At the same
time, the owner remains responsible for ensuring its products are made in
compliance with CGMP even when a quality agreement assigns a particular
manufacturing activity to the contract facility. After finding problems at a
contract facility, such as the ones described in the cases above, FDA might
determine that it is appropriate to inspect the owner. The owner could also be
in violation of CGMP related to its failure to oversee the contract facility’s
manufacturing activities.
B.
CGMPs
Apply to all Contract Facilities, Including Analytical Testing Laboratories
Case 3: Unreliable Data in Laboratory Records and Test Results
In this
scenario, an owner contracts with a facility for analytical testing services.
The contract facility repeatedly reports passing results in its CGMP records
when actual analyses indicated failures. The contract facility also fails to
report accurate results to the owner, who is the finished drug product
manufacturer.
When FDA
inspects the owner, it finds that despite having a written procedure requiring
a site audit of contract facilities every 2 years, the owner has not audited
the analytical testing facility.
Case 4: Contracted Analytical Testing Laboratory and Method Validation
An owner
contracts with a facility to perform stability testing and other analyses of
its newly approved drug. FDA approval and a quality agreement with the owner
require the drug to be manufactured using these processes, which are described
in the owner’s new drug application (NDA). The contract facility uses an
analytical method contained in the NDA but gets several out-of-specification
results. Also, the facility’s duplicate sample analyses occasionally point to
possible unacceptable variations in drug concentration. The facility
investigates the varying results and concludes that the failures are related to
the sample preparation techniques but does not clearly identify the problem. Despite
this, the contract facility continues to use the noncompliant method to test
the product.
When FDA
inspects the contract facility, it finds that the facility failed to fully
investigate the problems and implement corrective actions. The contract facility
claims that because it used the owner’s analytical method as specified in the
product application, it is not responsible for investigating and implementing
corrections related to it.
In both of
the cases above, FDA might conclude that the contract facilities are
responsible for violating CGMP applicable to the laboratory activities they
perform. FDA could also conclude
that the
owners are responsible for CGMP violations. Analytical testing laboratories are
responsible for operating in compliance with CGMP regardless of quality
agreements they may have with owners. They must employ adequate controls to
ensure that data and test results are reliable and maintained in accordance
with CGMP requirements. It is the owner’s responsibility to review this
information from the contract facility to decide whether to approve or reject
product for release and distribution.26
No matter who
tests the products, the owners’ quality units are ultimately responsible for
ensuring that the products are manufactured in accordance with CGMP. A quality
agreement does not change that. FDA could cite the owners in cases 3 and 4
further for failing to evaluate, qualify, audit, and monitor their contract
facilities.
C.
Owners
and Contract Facilities Perform Change Control
Activities
Case 5: Approving or Rejecting Changes That Affect Product Quality and
CGMP Compliance
A contract
facility informed the owner about obvious powder segregation issues. The
contract facility had attempted to correct the problem by making changes to the
equipment, but then determined that the issues could not be fixed without
process redesign and component changes. Under their quality agreement, the
contract facility could not implement these changes without the owner’s
approval. The owner refused to approve the recommended changes, so the contract
facility continued manufacturing the product using the flawed process and is
therefore not compliant with CGMP.
Case 5
illustrates the responsibilities of both owners and contract facilities when
change control issues are in question. Owners may be reluctant to approve
changes recommended by contract facilities, even if changes are necessary to
continue manufacturing the drug in compliance with CGMP.
VI.
RECOMMENDATIONS
Owners and
contract facilities can draw on quality management principles to carry out the
complicated process of contract drug manufacturing by defining, establishing,
and documenting their activities in drug manufacturing operations, including
processing, packing, holding, labeling operations, testing, and quality control
operations. Accordingly, FDA recommends that owners and contract facilities
implement written quality agreements as tools to delineate manufacturing
activities for ensuring compliance with CGMP.
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