Documentation of CGMP Approach

The documentation needed to demonstrate compliance with part 4 should be easily accessible
by manufacturers of combination products, and they should have it on hand in case an FDA
inspection is necessary. The quality system documentation for the facility should list the
CGMP operating system for the combination product(s) produced there, and the manufacturer
should give investigators access to this data at the start of an investigation. For combination
product producers using a simplified approach, inspection of the underlying CGMP operating
system, which is 21 CFR part 210/211 or 21 CFR part 820, will frequently be consistent with
current compliance systems and guidelines (See Part II.B.1 above). FDA seeks to apply
certain provisions from the non-base system using the compliance program and related policy
features.

Before the publication of part 4, manufacturers of combination goods already required to

demonstrate compliance with the relevant CGMP requirements for each component element
of their combination product. The CGMP processes and procedures used by manufacturers
must be compliant with the legislative framework outlined in section 4 of this publication. If
operating system changes are necessary to comply, the actions taken by manufacturers to
maintain the safety and effectiveness of their products should be documented. The
manufacturers must be prepared to discuss their plan during inspections.

Manufacturers of combination products should state in premarket filings whether they are
employing a streamlined approach, and if so, state whether it is based on device QS
regulations or drug CGMPs. This is because manufacturers of combination products must
address CGMP concerns as part of premarket review. For each relevant facility, the CGMP
approach should be indicated in premarket submissions. For NDAs, BLAs, and ANDAs,
paperwork at their facilities should include a description of the CGMP strategy.

The U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA),
and other regulatory bodies have released Good Manufacturing Practice (GMP) guidelines to
guarantee that drug device combination products are manufactured and controlled in a
manner that complies with established quality standards. The design, development,
manufacture, testing, and labeling of products as well as their labeling are all covered by the
GMP rules for pharmaceutical device combination products. These guidelines emphasize the
need for a comprehensive quality management system that includes the following:
 1. Design Controls: The guidelines require that the design of drug device combination
products be based on sound engineering principles and that design changes be
properly documented, reviewed, and approved.
2. Process Controls: The guidelines require that manufacturing processes be validated,
monitored, and controlled to ensure that the final product meets established
specifications.
3. Quality Controls: The guidelines require that quality controls be established and
maintained throughout the manufacturing process, including the testing of raw
materials, intermediates, and finished products.
4. Labeling Controls: The guidelines require that labeling be accurate, informative, and
in compliance with applicable regulations.
5. Documentation Controls: The guidelines require that all manufacturing and quality
control activities be properly documented and that records be maintained in a manner
that allows for traceability and accountability.

These guidelines apply to a wide range of drug device combination products, including those
that are implantable, injectable, inhalable, or topical. Manufacturers are required to
implement and maintain a quality system that complies with these guidelines and that is
subject to regular inspection by regulatory authorities.

GMP guidelines for drug device combination products are intended to ensure that these
products are manufactured and controlled in a manner that meets established quality
standards, and that they are safe and effective for their intended use.

The USFDA regulatory guidelines for drug device combination products are a set of
regulations and guidelines that govern the development, manufacturing, and marketing of
combination products that include both a drug and a device. These guidelines are designed to
ensure that such products are safe, effective, and meet the standards of quality set by the
FDA.

The USFDA regulatory guidelines for drug device combination products cover a wide range
of topics, including:

1. ‘Classification: The FDA classifies drug device combination products into one of
three categories based on the primary mode of action of the product.’
2. ‘Pre-market requirements: Depending on the category of the product, the FDA may
require pre-market approval through either a New Drug Application (NDA), a
 Biologics License Application (BLA), a Premarket Approval Application (PMA), or a
510(k) clearance.’
3. ‘Current Good Manufacturing Practices (CGMPs): The FDA requires that
manufacturers of drug device combination products follow the CGMPs to ensure that
the products are consistently produced and controlled according to established quality
standards.’
4. ‘Labeling: The FDA requires that the labeling of drug device combination products is
accurate, informative, and in compliance with applicable regulations.’
5. ‘Post-market requirements: The FDA requires manufacturers of drug device
combination products to monitor the product's performance after it is marketed and to
report adverse events to the FDA.’
6. ‘Device-specific requirements: Depending on the device component of the
combination product, additional regulations may apply. For example, if the device is a
medical device that requires a 510(k) clearance, then the FDA's regulations for
medical devices will also apply

Advice in brief
Under section 503(g) of the FD&C Act and 21 CFR part 3, a combination product is defined
as a product composed of two or more distinct types of medical products (i.e., a medication,
device, and/or biological product). The constituent pieces of the combination product are the
medications, equipment, and biological products that are incorporated in it.

• A product made up of two or more regulated components, such as drug/device,

biologic/device, drug/biologic, or drug/device/biologic, that have been physically,
chemically, or otherwise merged or blended to form a single entity (for example, a prefilled
syringe or drug-eluting stent);

• two or more distinct products packaged together in a single package or as a unit and made
up of drug and device products, device and biological products, or biological and drug
products; a co-packaged combination product, such as a surgical or first-aid kit containing
bandages and an antiseptic drug;

Since each of these kinds of combination products is subject to both drug CGMPs and device
QS requirements, this is used to concentrate on specific CGMP difficulties related to 21 CFR
4.4 CGMP rules. The focus is on how a business can follow the 21 CFR 4.4(b)(1) device QS
regulatory requirements if their CGMP operating system is streamlined and medication-
based.

A drug or device that is intended to be used only in conjunction with another approved,
individually specified drug or device, where both are required to achieve the intended use,
indication, or effect, and where the labelling of the approved product would have to be
changed if the proposed product were approved.

• Any investigational drug, device, or biological product packed separately and intended to
be used only in conjunction with another specifically designated investigational drug, device,
or biological product when both are required to achieve the intended use, indication, or effect
(also a cross-labelled combination product).

For its regulation, a combination product is allocated to an Agency center with primary
jurisdiction (i.e., the point of contact). Section 503 requires that a combination product be
assigned to a lead center depending on which component portion delivers the predominant
mode of action of the combination product (PMOA). If, for example, PMOA of a device
biological product drug combination is due to the biopharmaceutical, the center responsible
for premarket evaluation of such a biopharmaceutical would have main responsibility for the
combination product's regulation.

To accomplish appropriate, consistent regulation, the Agency center with primary authority
collaborates with other Agency centers. If investigators are unsure about product
classification or disapprove with a center about which center is the lead for a type of product,
they may submit a request for designation (RFD) to FDA to achieve a binding classification
and/or assessment persistence, or a Pre-RFD to obtain feed back about your manufacturer's
classification and/or assignment, including information about the preparation of an RFD.
While sponsors may recommend the categorization and/or assignment they consider will
apply for a pre-RFD and must do so for an RFD, the final determination is made by the
Office of Pharmaceutical Formulations (OCP) with input from the necessary Agency
components.

Basics of Interacting

In collaboration with the FDA The lead center is a sponsor's primary point of contact as well
as the Agency's focal point for communicating FDA's views to the sponsor. Sponsors have
access to and will employ the lead center's premarket processes and procedures, including
pre-submission talks and other avenues for obtaining Agency comments. 7 While this general
approach is available and will be used for all pharmaceutical formulations, cross-labeled
combination products that seek distinct marketing approvals for the constituent parts (e.g., a
new drug application (NDA) for the drug as well as a premarket notification (510(k)) for the
device) may raise distinct concerns.

Regardless of the comments asked, all conversations with the FDA for all these combination
medications will be conducted through the principal center before they make separate
marketing authorisation filings. The sponsor(s) may decide to consult with centers about how
to guarantee efficient and coordinated engagement during the product registration filing
evaluation process (e.g., in light of the differing user fee performance goals associated with
submission types for each constituent part). 8 Section 503(g)(8)(C)(iv) states that the centers
will ensure that conferences between the FDA and sponsors are attended by appropriate
overview staff from each center in light of the significant topics and the meeting's intent, and
that consulting institutes complete their trade mark reviews in a timely manner, in
collaborative efforts with OCP when necessary..

According to Section 503(g)(8)(C)(iii), Agency communications addressing the review from

the lead center are regarded as communications on behalf of all centers involved in the
review, to the extent permitted by applicable law and the requirements of all impacted
centers. As a result, before sending out such signals, centers must work together as needed.

According to section 503(g)(8)(C)(v), sponsors may submit written requests for OCP
representatives to attend conferences or other events relating to their products, or for OCP to
otherwise engage in regulatory matters relating to the product. Agency and sponsor
components. There are various available dispute resolution procedures for the substance of
such reviews.

This discussion is intended to highlight only certain issues that a combination product might
raise relating to the CGMP provisions specified in 21 CFR 4.4(b), and considerations for
addressing these issues. The discussion may help to clarify how the CGMP regulations stated
here should be understood in regard to various types of combination products as well as the
types of combination goods that are included in the scenarios. Nevertheless, this session does
not fully analyze the CGMP challenges that must be overcome for the products shown in the
scenarios or other kinds of combination goods. The fictitious examples listed below do not
account for the particular difficulties that particular objects may present. The Agency
suggests that if producers have special questions concerning their unique products, they seek
assistance from the lead center for the product or OCP, as necessary.

A. Prefilled syringe
(for understanding lets say company is manufacturer)
1. ‘The manufacturer already has marketing approval for the medicinal medication, and
it plans to get it for the combo product as well. The medication's formulation won't be
altered in any way. A supplier who also produces finished syringes from the same
parts will sell the producer off-the-shelf syringe component parts. The prefilled
syringe will be packaged, labeled, and distributed by the manufacturer after the parts
of the syringe are assembled in a facility under its control.’

At the manufacturing facility, a pharma CGMP operational system is already in place.

Prefilled syringes must comply with both the medical device QS regulation and the drug
CGMPs since they fall under the definition of a single-entity drug combination under 21 CFR
3.2(e)(1). Manufacturer decides to use the drug's CGMP-based streamlined technique and
construct a CGMP operating system in compliance with 21 CFR 4.4. (b). While the
manufacturer must ensure that its operating system conforms with the drug CGMPs for this
product, incorporating all of the questions presented by the inclusion of the device constituent
part, this example focuses on factors for illustrating the fulfilment of the demands from the
device QS regulation as specified in 21 CFR 4.4. (b).

2. ‘examining the apparatus The requirements of QS regulation The device Quality

System (QS) requirement, as described in 21 CFR 4.4, must also be met by the
manufacturer if they opt to apply the medicine CGMP-based streamlined method, as
stated in 21 CFR 4.4(b)(1) (b). The combination product producer should take into
account the factors and activities mentioned in this discussion in order to adhere to the
requirements of each of these provisions of the device QS regulation.’
3. ‘Controlling Responsibility 21 CFR 820.20 While the FD&C Act's Section 501 (21
U.S.C. 351) and other regulations, as well as 21 CFR 211.22, 211.25, and 211.180,
lay forth standards for management accountability, Manufacturer must ensure that its
CGMP operating system exhibits compliance with the specific requirement in 21 CFR
820.20. The design and control considerations for a prefilled needle with a
biopharmaceutical are broadly similar to those covered in the example, even though
 some additional issues, such as the biological product's interplay with the syringe
components and the impact of device viscosity on delivery, may be more frequent.
116 of CFR part 4 Consult 21 CFR 4.4(b) (1).’

Manufacturer will, for example, review its existing CGMP operating system to assess
whether changes are needed to comply with this provision. As part of this review,
management with executive responsibility for Manufacturer will review the facility’s quality
policy and develop and implement appropriate oversight procedures, if such procedures are
not already in place, to ensure that both the policy and oversight are adequate. The oversight
procedures will include clear delineation of the personnel to whom management with
executive responsibility is delegating responsibility For instance, the company will determine
whether changes to its present CGMP operating system are necessary to satisfy this criterion.
Management with executive responsibility for Manufacturer will examine the facility's
quality policy as part of this evaluation to ensure that the policy and oversight are adequate,
and if such procedures are not already in place, they will establish and apply them. The
supervision processes will clearly identify the people to whom management with executive
responsibility is assigning responsibility for implementing the quality policy (including its
translation into methods and procedures) and the CGMP operating system for this product at
the plant. for implementing the quality policy (including translation into methods and
procedures) and the CGMP operating system for this product at the facility.

b) ‘Controls for Designs, 21 CFR 820.30 The manufacturer of the combined product is in
responsible of developing and enforcing procedures for design control activities. The
prefilled syringe in this case is produced by Manufacturer, who is also the owner. As a result,
the Manufacturer is in charge of the design control activities for the syringe that is a part of
the combination product in addition to having overall responsibility for the combination
product. On the other side, the manufacturer buys the syringe components from the syringe
supplier, who uses the same components to make finished syringes. As a result, the
manufacturer may be allowed to use design control papers from the supplier of finished
syringes' design controls that are particular to syringes. The only change to the medicine is its
location in the syringe, therefore it enters the development internal control as an input
towards the syringe's design. This is done to make sure that the design of the syringe
sufficiently accounts for the characteristics of the medication, as indicated below.
To determine what new problems are brought on by using the syringe with the drug, and to
determine whether any further design control actions are required as a result, it would be
appropriate for the manufacturer to review the design control information from the syringe
supplier as a first stepOnly the effectiveness of the hypodermic needle as a container or
cessation to preserve this same drug and the extent to and which interaction between both the
syringe and the drug may modify its achievement as a delivery mechanism are supplementary
design considerations that may be made, for instance, if the maker can demonstrate it. The
Manufacturer shall at all times ensure that 21 CFR 820.30 is complied with and that all
design factors for the combined product are taken into account.’

The manufacturer would probably need to do more complex design control procedures for the
syringe if the source of the parts of the machine lacks design control information. For
example, Manufacturer would need to perform device-specific verification testing to confirm
that the syringe meets necessary specifications for plunger force or other parameters if the
syringe component supplier has not conducted such testing suitable to enable leveraging.

i. Design verification and validation

“The manufacturer must implement design verification and validation methods to confirm
that the combined product satisfies all design input criteria, including user needs and intended
uses, after establishing design outputs for all design inputs. Bench testing the drug delivery
from the prefilled syringe to ensure repeatable and accurate drug delivery, shock and
vibration testing of the packaged prefilled syringe to ensure no damage or loss of integrity in
shipping, confirming that expected users can successfully follow the instructions for use,
additional human factors studies, biocompatibility testing, drug and syringe compatibility
studies, and lead (i.e., needle, needleless). These activities would be documented in the DHF
pursuant to 21 CFR 820.30(j) and would be subject to design change and review
requirements pursuant to 21 CFR 820.30(e) and (i).”

ii. Design changes

Additionally, the manufacturer must have policies in place to guarantee that any
modifications to design specifications are recognized, recorded, validated and/or confirmed,
reviewed, and approved before being put into practice. The initial risk analysis will be
reviewed, the new design inputs and outcomes will be approved, and the design change will
be reviewed and approved, among other things. For example, before replacing a material used
in the hypodermic that comes into touch with the medicine, Manufacturer will conduct
validation activities to guarantee that no deterioration of performance requirements will occur
before the end date for the drug combination as a consequence of the alteration of materials.
Similar to this, every modification to the drug's formulation will involve design control
procedures such as verification to ensure that the new formulation does not impair the
syringe's functionality. The DHF would have to incorporate all of this data.

iii. Design history file

The DHF may include references to information that is located elsewhere as well as pointers
to that information, provided that the reference or link is specific enough to enable speedy
access to the needed data. Reference 21 CFR 820.30 (g). 121 Reference 21 CFR 820.30 (i).
Changes to materials that come into touch with a medicine, such as those caused by
regulations for stability testing and expiration dates, may have an impact on its CGMP (21
CFR 211.137 and 21 CFR 211.167). Manufacturers may, wherever practicable, use the
information acquired in order to satisfy these 21 CFR 211 requirements when determining
what verification processes are required to comply with 21 CFR 820.30. Reference 21 CFR
820.0. (j).

As required, especially for inspections, accessible. For instance, the combination product
DHF may be supported by some portions of the design documentation provided by the maker
of the syringe component. Such syringe-related data may be kept at the syringe provider's
facility so long as the required documentation is easily accessible during the manufacturer
inspection. By agreements with the syringe provider, the manufacturer will guarantee that
access to such documentation is available (21 CFR 820.50). In order to design the
medication's inclusion into a prefilled syringe, the DHF may resort to drug development
records that were already in existence and use those records as input in the construction of the
combination product (though such drug-only development is not itself subject to design
controls).

c) 21 CFR 820.50, Purchasing Controls

In accordance with 21 CFR 820.50.124, the manufacturer is responsible for managing all of
its purchasing decisions, including acquisitions of syringe components. If the material of the
syringe barrel and plunger is crucial to ensuring that the drug is not adversely affected, the
manufacturer will design purchasing agreements with the supplier of syringes to ensure that
the manufacturer is informed of any changes to this material prior to the implementation of
the change. Similarly, Manufacturer shall exercise the necessary controls over the
sterilization service provider if Manufacturer sends the prefilled syringe to an outside facility
for terminal sterilization.

d) 21 CFR 820.100, Corrective and Preventive Actions

Manufacturer is required to establish and maintain CAPA procedures for the combination
product. Following is the examples of issues that might arise and exemplary steps for
addressing them:

Example : To ensure that the correct dosage of medication is being dispensed into the
syringe, the manufacturer has put up in-process manufacturing verification procedures. The
information from this verification is then examined for a potential nonconformity. The
company starts a CAPA to look into the issue after observing an increase in nonconformities
connected to the dosage of medicine placed in the syringe. The manufacturer investigates the
reason of the improper fill volume and determines that filling machine maintenance methods
are to fault. The manufacturer revises the maintenance guidelines and does
verification/validation testing to make sure the improvements fix the issue and don't lead to
new ones.

e) 21 CFR 820.170, Installation and 820.200, Servicing Installation and servicing

requirements would not apply to the prefilled syringe because the product does not require
installation or servicing activities.

REFERENCES
Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements
for Combination Products FINAL GUIDANCE. (2017). Available
at: https://www.fda.gov/media/90425/download.

Research, C. for D.E. and (2021). Facts About the Current Good Manufacturing Practices
(CGMPs). FDA. [online] Available at: https://www.fda.gov/drugs/pharmaceutical-quality-
resources/facts-about-current-good-manufacturing-practices-cgmps#:~:text=CGMPs
%20provide%20for%20systems%20that.

Dimitrova, M.N., Bee, J.S., Lu, L. and Fernandez, J.E. (2018). Development of Prefilled
Syringe Combination Products for Biologics. Challenges in Protein Product Development,
pp.203–224. doi:https://doi.org/10.1007/978-3-319-90603-4_9.
Commissioner, O. of the (2019). Postmarketing Safety Reporting for Combination Products.
[online] U.S. Food and Drug Administration. Available at: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/postmarketing-safety-reporting-combination-
products.

Badkar, A., Wolf, A., Bohack, L. and Kolhe, P. (2011). Development of Biotechnology
Products in Pre-filled Syringes: Technical Considerations and Approaches. AAPS
PharmSciTech, 12(2), pp.564–572. doi:https://doi.org/10.1208/s12249-011-9617-y.

Kiang, P. (2016). Combination Product Development -Pre-filled Syringe and Injection

Devices. [online] Available at: https://www.pda.org/docs/default-source/website-document-
library/chapters/presentations/west-coast/combination-product-development---pre-filled-
syringe-and-injection-devices.pdf?sfvrsn=3578848e_4.