Combination Products

1
Combination Products

• Presented by Karen S. Ginsbury
• For IFF
• March 2014

2
Purpose of the Seminar

• Review regulatory requirements
• Medical device
• Drug
• Biologicals
• Human Cell and Tissue Therapy Products
• Combination Products
• Other?
• Quality System What is appropriate

3
Regulation of Drugs and Devices QSR / cGMP
Regulations

• LEGISLATION
• REGULATION
• GOOD MANUFACTURING PRACTICE
• CURRENT

4
What is a Combination Product

• 21 CFR Part 3
• MEDDEV
• Lets take a look

5
MED DEV Not legislation
6
Combination products medical device, drug or
both?

• Products that share the attributes of two
  categories of products
• In each scenario below, would you consider the
  combination product a medical device, medicinal
  product or equally both?

7
Drug Product, Device or Both?

• Contact lens care product that is indicated to
  disinfect, clean, rinse and hydrate contact lens
• Water to be used for injections, IV fluids and
  plasma volume expanders
• Syringe needle applicator and insulin form a
  single integral unit that is intended exclusively
  for use in the given combination for one-time
  administration of insulin and is not reusable
• Bone void filler to repair bone defects by which
  the primary action is a physical means (matrix)
  to provide a volume and scaffold for
  osteoconduction, where an additional medicinal
  substance is incorporated to assist and
  complement the action of the matrix by enhancing
  the growth of bone cells

8
Drug Product, Device or Both?(In the EU NOT in
USA)

• Contact lens care product that is indicated to
  disinfect, clean, rinse and hydrate contact lens
  MD Accessory
• Water to be used for injections, IV fluids and
  plasma volume expanders Drug Product
• Syringe needle applicator and insulin form a
  single integral unit that is intended exclusively
  for use in the given combination for one-time
  administration of insulin and is not reusable
  Drug Product
• Bone void filler to repair bone defects by which
  the primary action is a physical means (matrix)
  to provide a volume and scaffold for
  osteoconduction, where an additional medicinal
  substance is incorporated to assist and
  complement the action of the matrix by enhancing
  the growth of bone cells Medical Device

9
In EU

• A combination product is regulated in Europe by
  either the Medical Device Directive MDD 93/42/EEC
  or the Medicinal Product Directive 2001/83/EC
• A general rule is that the primary mode of action
  (or function) of the product dictates how it is
  regulated
• Therefore, a product never can be both a
  medicinal product and possess CE Marking

10
http//www.fda.gov/MedicalDevices/
11
Device Advice
12
What is a Combination Product
13
The Rule
14
Cross-labeled orCo-Packaged and Single-entity
15
Streamline
16
Add to GMP Regs 21 CFR 211
17
Add to QSR 21CFR Part 820
18
Questions put to FDA
19
More Questions
20
Combination Products

• This guidance has been prepared by the Office of
  Combination Products in the Office of the
  Commissioner in cooperation with the Center for
  Biologics Evaluation and Research (CBER), the
  Center for Drug Evaluation and Research (CDER),
  and the Center for Devices and Radiological
  Health (CDRH) at the Food and Drug
  Administration.

21
cGMP

• For purposes of this guidance document, the term
  current good manufacturing practice refers to the
  current good manufacturing practice regulations
  for drugs and most biological products under
• 21 CFR Parts 210 and 211,
• 21 CFR Parts 600-680 for certain biological
  products
• 21 CFR Part 820 QSR for devices

22
What is a combination product?

• A product composed of any combination of
• a drug and a device
• a biological product and a device
• a drug and a biological product
• a drug, device, and a biological product

23
21CFR 3.2(e)

• A combination product includes
• A product comprising two or more regulated
  components that are physically, chemically, or
  otherwise combined or mixed and produced as a
  single entity
• Two or more separate products packaged together
  in a single package or as a unit
• A drug, device, or biological product packaged
  separately that according to its investigational
  plan or proposed labeling is intended for use
  only with an approved individually specified
  drug, device, or biological product where both
  are required to achieve the intended use
• Any investigational drug, device, or biological
  product packaged separately that according to its
  proposed labeling is for use only with another
  individually specified investigational drug,
  device, or biological product where both are
  required to achieve the intended use, indication,
  or effect.

24
CGMP Section 501 Food Drug and Cosmetics Act

• Section 501 authorizes FDA to establish current
  good manufacturing practice to avoid adulteration
  of drugs
• Adulteration includes a failure of the drug,
  biological product, or device to be manufactured
  in accordance with current good manufacturing
  practice, regardless of whether the product is
  actually deficient in some respect.

25
Purpose of GMP

• Current good manufacturing practice regulatory
  provisions are intended to ensure that the drug,
  biological product, or device is not
  adulteratedso as
• to ensure the product possesses adequate
  strength, quality, identity, and purity of a drug
  or biological product
• to ensure compliance with performance standards
  for a device.

26
21 cfr Part 820 QSR

• A General
• B Quality System Requirements
• C Design Controls
• D Document Controls
• E Purchasing Controls
• F Identification Traceability
• G Production and Process Controls
• H Acceptance Activities
• I Non Conforming Product

• J CAPA
• K Labeling and Packaging Controls
• L Handling, Storage, Distribution
  Installation
• M Records
• N Servicing
• O Statistical Techniques

27
21 cfr part 211GMP for Finished Pharmaceuticals

1. General
2. Organization Personnel
3. Facilities
4. Equipment
5. Component Controls

1. Production Controls
2. Packaging Controls
3. Warehousing
4. Laboratory Controls
5. Documentation
6. Returns and Recalls

28
CGMP vs QSRCombination Drugs Guideline

• Considerable overlap in the CGMP and QS
  regulations
• Both establish requirements for management,
  organization, and personnel
• Both require documentation and record keeping
• Both allow flexibility for manufacture
• FDA considers the CGMP and the QS regulations to
  be similar they are meant to achieve the same
  goals
• Prior to combining product follow QSR or cGMP

29
(No Transcript)
30
Risk Management

• What could go wrong
• With the drug
• With the device
• With the biological
• With the combination

31
Quality Management

• Requires management involvement and commitment
  resources
• For investigational drugs may have same
  individual performing Quality functions who is
  performing production or other functions. In
  this case, also have independent review
• Always involves SOPs, documentation and control
  of activities

32
Personnel Training

• All personnel should have the education,
  experience and training or any combination
  thereof to enable that person to perform the
  assigned function
• In particular, personnel should have the
  appropriate experience to prepare the
  investigational product and be familiar with QC
  principles and acceptable methods for complying
  with the statutory requirement of CGMP

33
Facilities and Equipment

• Sufficient space, clean environment, appropriate
  construction
• Appropriate lighting, ventilation, and heating
• Appropriate cooling, plumbing, washing, and
  sanitation
• Appropriate air handling systems (e.g., laminar
  flow hoods) to aid in preventing contamination
  and cross-contamination of product
• Appropriate equipment that will not contaminate
  the product not be reactive, additive, or
  absorptive with product is properly maintained,
  calibrated, cleaned, and sanitized at appropriate
  intervals following written procedures
• Prevent contamination and cross-contamination

34
Purchasing Controls

• Written procedures describinghandling, review,
  and acceptance and control of components used in
  the production of an investigational product
• Components should be e.g. segregated, labeled,
  until examined or tested, as appropriate, and
  released for use in production
• Handle and store to prevent degradation or
  contamination
• Keep records of receipt and use
• Acceptance criteria, COAs and identity testing

35
QC Controls

• Test methods scientifically sound
• Validation? Stability indicating?
• OOS results MUST have a written procedure and
  follow it
• Written, approved specifications
• Calibrated, qualified lab equipment
• Sample log-in
• Record keeping
• Standards.must be valid

36
Documentation

• Production records
• Laboratory records
• Deviation reporting
• Change control and audit trails
• Batch release records

37
Packaging Controls

• May be particularly complex for clinical trials
  because of placebo
• Make sure no previous product
• Avoid mix-ups
• Document line clearance

38
Statistical Controls

• Use of valid statistical methods
• Define in written procedures
• DO NOT select the method AFTER you have the data
• May need assistance of statisticians beyond those
  within the company

39
Validation

• Confirmation by examination and provision of
  objective evidence that the particular
  requirements for a specific intended use can be
  consistently fulfilled
• 21cfr 820.3 (Definitions)

40
Validation

• Validation Providing documented evidence, in
  accordance with a pre-approved protocol that a
  system, equipment, process, analytical method
  does what it is designed to do repeatedly and
  reliably. Have pre-determined acceptance
  criteria / specification
• CDER / EU for drugs

41
Process Validation

• Establishing by objective evidence that a
  process consistently produces a result or product
  meeting its predetermined specifications
• 21cfr 820.3 (Definitions)

42
Design Validation

• Establishing by objective evidence that device
  specifications conform with user needs and
  intended use(s).
• 21cfr 820.3 (Definitions)

43
Verification

• Confirmation by examination and provision of
  objective evidence that specified requirements
  have been fulfilled
• 21cfr 820.3 (Definitions)

44
Subpart C - Design Controls - 2

• 820.30 (g) Design Validation
• Establish and maintain procedures for validating
  the device design.
• Performed under defined operating conditions on
  initial production units, lots or batches.
• Ensure that devices conform to defined user needs
  and intended uses
• include testing of production units under actual
  or simulated conditions of use

45
Subpart C - Design Controls - 3

• 820.30 (g) Design Validation cont/
• Include software validation and risk analysis,
  where appropriate
• Results including identification of the design,
  methods, date and individuals performing the
  validation documented in the DHF

46
21 cfr 820.75 Process Validation

• Where the results of a process cannot be fully
  verified by subsequent inspection and test, the
  process shall be validated with a high degree of
  assurance and approved according to established
  procedures

47
21 cfr 820.75 Process Validation

• A man who makes a mistake and does not correct it
  is making another mistake(Confucius)
• When changes or process deviations occur, the
  manufacturer shall review and evaluate the
  process and perform revalidation where
  appropriate.

48
Change Control

• Remember Remedia It wasnt a change it was an
  improvement!
• All changes are initiated as improvements
• All changes have the potential to invalidate a
  valid process

49
21 cfr 820.70 (b)

• Production and process changes
• Establish and maintain procedures for changes to
  a specification, mehtod, process or procedure
• Changes should be verified or where appropriate
  validated before implementation and these
  activities documented.

50
Thank You