Regulation of Drug
Manufacturing
Neil P. Di Spirito, Esq.
Rumberger, Kirk & Caldwell
ndispirito@rumberger.com
Define Small/Midsize Drug
Companies
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Sales of $25million to $200million
75 to 150 employees
10,000 to 1000,000 sq. ft. of plant space
3 to 6 products on average
Privately or Publicly held
Specialty or underserved markets
From topicals to very high-tech biopharms
(produced in smaller quantities) and Orphan
Drugs
Define Small/Midsize Drug
Companies
• Usually no or general (nonregulatory/compliance) in-house counsel
• Newer less experienced Quality Units
• Diversity of Issues
• Capable of handling their regulatory/compliance,
business (i.e. licensing, contracts,etc.), litigation
and enforcement
• Need background in science, business and law
(undergrad science with MBA and Law Degree)
When FDA Knocks
Hi, I’m from the
Government…
and I’m here
to help…
•Got
it?!
•It is a crime to
refuse an
authorized
FDA Inspection
Challenges to Small/Midsize Drug
Companies
• Understanding drug current Good
Manufacturing Practices (cGMPs), and
defining "adulteration" and "misbranding"
• Review the different types of inspections
• Explore the elements of a 483 observation
and the components involved with closing
out an inspection
Two Major Challenges to
Small/Midsize Drug Companies
• Adulteration---methods or processes used are
not in conformance with good manufacturing
practices
– (FDCA §501 (a)(2), 21 U.S.C. §351 (a)(2)(b),
21 CFR Part 210 & 211);
• Misbranding--- provisions can pertain to
materials that are physically distant from the
product or its container (ads making improper
claims run in journals).
• labeling is false or misleading
– (FDCA §502 a), 21 U.S.C. §352(a));
Good Manufacturing Practice
(GMP)
• Good manufacturing Practices were implemented by the
FDA to ensure that Drug Products are manufactured in
an appropriate and safe way
– (21 CFR 210 & 211)
• FDCA grants FDA authority to ensure compliance with
current GMP
– (cGMP) (§ § 301(a), 501(a)(2)(b); 21 USC § § 331(a);
351(a)(2)(b)
• A Drug is adulterated if found not to be manufactured
according to cGMP’s
– (§ § 301(a), 501(a)(2)(b);
Good Manufacturing Practice
(GMP)
• A drug can meet its specifications, contain no
detectable impurities, be both safe and effective
and still be considered adulterated if the
manufacturing was not in compliance with
cGMP’s.
– (FDCA §501 (a)(2), 21 U.S.C. §351 (a)(2)(b),
21 CFR Part 210 & 211);
• Quality should be built into the product and
testing alone cannot be relied upon to ensure
product quality”
– (FDA Guidance for Industry, Sept. 2006)
Good Manufacturing Practice
(GMP)
• The role of the FDA is to determine which
practices in use are “good” and enforce
those.
• FDA does not prescribe “how to make products”,
but requires manufacturers to do so.
• Must establish: Procedures which assure the
drug is manufactured in a way to consistently
meet specifications.
GMP: Current not Static
• Reference point not FDA imposed
• In use by various manufacturers
• FDA assess practices as “Good” and enforces
those practices
• Advance state of the art
• Need not be widely prevalent to become
“standard”
SOP’s Source of Issues for
Small/Midsize Companies
Production Process and Controls
• Requires written procedures (SOP’s and validation) to
conduct batch production and processing in a way
ensuring the accuracy of:
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–
–
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Identity
Strength
Purity
Quality
• (21 CFR 211(f))
• Attorney review to ensure compliance with latest
Policy/Regulations of FDA (Consultants not always up to
date)
Laboratory Controls
Laboratory Controls:
• Requires the design and continued use of Lab
procedures to maintain continuous control of lab
processes.
– (21 CFR Part 211(i))
• These are the standards, specifications, and test
procedures that ensure the tested drugs are of
the appropriate identity, strength, quality and
purity.
– (21 CFR Part 211(i))
Challenges
(OOS)
• No or inadequate procedures for handling
“out of specification” (“OOS”) situations,
failure investigations and “corrective and
preventive actions” (CAPA) are amongst
the most frequently found deviations in
FDA warning letters. Most companies
have procedures but either they are not
adequate or are not followed.
Challenges
Process
Process validation for drugs (finished
pharmaceuticals and components) is a
legally enforceable requirement under
section 501(a)(2)(B) of the Act (21 U.S.C.
351(a)(2)(B))
Method
process of demonstrating that analytical
procedures are suitable for their intended
use and that they support the identity,
strength, quality, purity and potency of the
drug
Validation Processes
• The foundation for process validation is provided
in § 211.100(a), which states that “there shall be
written procedures for production and process
control designed to assure that the drug
products have the identity, strength, quality, and
purity they purport or are represented to
possess...”
Validation Processes
• The CGMP regulations require that
manufacturing processes be designed and
controlled to assure that in-process materials
and the finished product meet predetermined
quality requirements and do so consistently and
reliably.
• The regulation requires manufacturers to design
a process, including operations and controls,
which results in a product meeting these
attributes.
Validation Processes
• The goal of validation is continual assurance
that the process remains in a state of control
(the validated state) during commercial
manufacture.
• A system or systems for detecting unplanned
departures from the process as designed is
essential to accomplish this goal.
Inspection Parameters
FDA Entitled to:
• Relevant information concerning whether drugs
(for human consumption) are:
–
–
–
–
Manufactured
Transported
Processed
Packed
• In accordance with the Act [FDCA]
– (704(a)(1); 21 USC 374(a)(1)
Inspection Parameters
NOT Entitled to:
• Financial Data
• Sales Data (other than shipping amounts)
• Pricing data
• Personnel data (other than the qualifications of
professional personnel)
• Research data (except for data required to be disclosed
under 21 USC 374 ‘approval data’)
• Internal audit, supplier audit, mgmt reviews)
Inspection Parameters
May Attempt to Obtain:
• Not statutorily or regulation authorized
– Affidavits from individuals (NEVER sign)
– Interview of employees (only those you
select)
– FDCA does not authorize investigators to
interview a company’s employees; (if so, with
counsel present)
• Managerial or non-managerial employees
Inspection Conclusions
• Post inspection discussion with investigators
(optional)
• Usually helpful to figure out FDA next steps
• Corrective actions disclosed
• Review of Form 483
Response to Form 483
• FDA expects a response from manufacturer on
each observation
– 15 business days
• Explain problem identified
• Proposed action or plan to prevent reoccurrence
of observation
• Use system preventative answers.
Establishment Inspection Report
• More detail description of 483 observations
• Generally tracks and expands on 483
• Classifies as “Voluntary Action Indicated” or
“VAI” or “Official Action Indicated” or “OAI”
• OAI usually indicates enforcement action of
some type (Warning Letter, etc.)
Establishment Inspection Report
• “RTS” Referred to State, local, or other federal
office.
– no federal jurisdiction over violation
– state action is the least involved and fastest
• “RTC” or Referred to Center
– No clear policy
– technical issues require Center review
Use of cGMP Violations in
Litigation
• Finding of adulteration based on failure to
comply with GMP’s even if product quality is fine
– Title 21 S. 351(a)(2)(B)
• Even if final product is “pharmaceutically
perfect,” manufacturing non-compliance will
deem product adulterated.
• Not only “Good” but “Current”
GMP: Current not Static
• Reference point not FDA imposed
• In use by various manufacturers
• FDA assess practices as “Good” and enforces
those practices
• Advance state of the art
• Need not be widely prevalent to become
“standard”
GMP: Proof in Litigation
• FDA must only prove :
– Manufacturer did not follow a particular practice
– Practice was deemed “Good” by FDA
• Cases:
– Provide flexibility…specific enough to assure drug is
safe and relaible…
» U.S. v. Bel Mar Labs, 284 F. Supp. 875
GMP: Proof in Litigation
• Non-USP mehtods used must be validated to
FDA satisfaction
– U.S. v. Barr Labs, 812 F. Supp. 458
• Enforced without expert testimony on the
currency or goodness of the practice
– Nat’l Ass’n PhARM. Manufacturers v. FDA, 637 F.2d
877
• FDA has authority to issue binding cGMP
regulations
– Nat’l Ass’n PhARM. Manufacturers v. FDA, 637 F.2d
877
Other Issues
• Establishment Registration And Drug
Listing
– §510(c), 21 U.S.C. §360(c); 21 C.F.R.
§207.21
• Drug Product Listing (Form FDA 2657)
– 21 C.F.R. §207.25
• Field Alert Reports (FAR)
– 21 CFR 314.81(b)(1)(i)
Field Alert Reports (FAR)
21 CFR 314.81(b)(1)(i) and (ii)
• Notify the district office within 3 working days
• Information may be provided by telephone, Fax,
E-mail or other rapid communication means
• prompt written follow-up (Form FDA 333)
• Internet Availability of Form 3331
When to engage a consultant/ Field
Alert Reports (FAR)
• Bacterial contamination
• Stability Issues:
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Product deterioration
Out-of-specification
Chemical changes in composition
Physical changes (i.e. pills crumble)
FAR’s on drug products foreign or domestic
Regulation of Drug
Manufacturing
Thank You
Neil P. Di Spirito, Esq.
Rumberger, Kirk & Caldwell
ndispirito@rumberger.com