5.

Do CGMPs require three successful process validation batches before a new active
pharmaceutical ingredient (API) or a finished drug product is released for distribution?

No. Neither the CGMP regulations nor FDA policy specifies a minimum number of batches to
validate a manufacturing process. The current FDA guidance on APIs (see guidance for
industry ICH Q7 for APIs) also does not specify a specific number of batches for process
validation.

FDA recognizes that validating a manufacturing process, or a change to a process, cannot be

reduced to so simplistic a formula as the completion of three successful full-scale
batches. The Agency acknowledges that the idea of three validation batches became prevalent
in part because of language used in past Agency guidance. FDA's process validation guidance
now recommends a product lifecycle approach. The emphasis for demonstrating validated
processes is placed on the manufacturer’s process design and development studies in
addition to its demonstration of reproducibility at scale, a goal that has always been
expected.

However, a minimum number of conformance (a.k.a. validation) batches necessary to validate

the manufacturing processes is not specified. The manufacturer is expected to have a sound
rationale for its choices in this regard. The Agency encourages the use of science-based
approaches to process validation.

In March 2004, FDA revised the Compliance Policy Guide (CPG) Sec. 490.100 on Process
Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to
Pre-Market Approval. The CPG describes the concept that, after having identified and
establishing control of all critical sources of variability, conformance batches are prepared to
demonstrate that under normal conditions and operating parameters, the process results in
the production of an acceptable product. Successful completion of the initial conformance
batches would normally be expected before commercial distribution begins, but some possible
exceptions are described in the CPG. For example, although the CPG does not specifically
mention concurrent validation for an API in short supply, the Agency would consider the use of
concurrent validation when it is necessary to address a true short-supply situation, and if the
concurrent validation study conforms to the conditions identified in the CPG (see paragraph 4,
a-c).

The conditions outlined in the CPG include expanded testing for each batch intended to
address a short-supply situation. Expanded testing conducted according to an established
validation protocol could provide added assurance that the batch meets all established and
appropriate criteria before the API is used in the finished drug product. Additionally,
confidence in the API manufacturing process may be gained by enhanced sampling (larger
sample size representative of the batch) and perhaps the testing of additional attributes.
Validated analytical methods are needed for testing every batch, including validation batches.
The Agency would also expect the manufacturer to use a validation protocol that includes a
review and final report after multiple batches are completed, even though the earlier batches
may have been distributed or used in the finished drug product.

References:

 21 CFR 211.100: Written procedures; deviations

 21 CFR 211.110: Sampling and testing of in-process materials and drug products
 Compliance Policy Guide Sec. 490.100 Process Validation Requirements for Drug
Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval
 FDA Guidance for Industry, 2001, ICH Q7 Good Manufacturing Practice Guidance for
Active Pharmaceutical Ingredients
 FDA Guidance for Industry, 2011, Process Validation: General Principles and Practices

6. Is it generally acceptable from a CGMP perspective for a manufacturer of sterile drug

products produced by aseptic processing to rely solely on ISO 14644-1 and ISO 14644-2 when
qualifying its facility?

No. It is generally not acceptable from a CGMP perspective for a manufacturer of sterile drug
products produced by aseptic processing to rely solely on ISO [International Organization for
Standardization] 14644-1 Part 1: Classification of Air Cleanliness (14644-1) and ISO 14644-2
Part 2: Specifications for Testing and Monitoring to Prove Compliance with ISO 14644-1 (14644-
2) when qualifying its facility. Rather, a manufacturer of sterile drug products produced by
aseptic processing should use these ISO standards in combination with applicable FDA
regulations, guidance, and other relevant references to ensure a pharmaceutical facility is
under an appropriate state of control. Consequently, appropriate measures augmenting ISO’s
recommendations (e.g., with microbiological data) would likely be expected for a firm to meet
or exceed CGMP in a pharmaceutical facility.

Please understand that 14644-1 and 14644-2 have superseded Federal Standard 209E, Airborne
Particulate Cleanliness Classes in Cleanrooms and Clean Zones (Federal Standard 209E). In
November 2001, the U.S. General Services Administration canceled Federal Standard 209E.

Although 14644-1 and 14644-2 are not FDA regulations or FDA guidance, the Agency
believes that they are useful in facilitating the international harmonization of industrial air
classification for nonviable particle cleanliness in multiple industries (e.g., computer,
aerospace, pharmaceutical). As such, FDA adopted these particle cleanliness ratings in the
2004 guidance for industry Sterile Drug Products Produced by Aseptic Processing–Current
Good Manufacturing Practice. However, due to the unique aspects of producing sterile drug
products by aseptic processing (e.g., microbiological issues), an aseptic processing
manufacturer should not rely solely on 14644-1 and 14644-2 when qualifying its facility.

References:

 U.S. Food and Drug Administration Web site

 International Organization for Standardization Web site
 ISO 14644-1 Part 1: Classification of Air Cleanliness
 ISO 14644-2 Part 2: Specifications for Testing and Monitoring to Prove Compliance with
ISO 14644-1
 FDA Guidance for Industry, 2004, Sterile Drug Products Produced by Aseptic
Processing–Current Good Manufacturing Practice
 21 CFR part 211: Current Good Manufacturing Practice for Finished Pharmaceuticals

16. Why is FDA concerned about proper sampling of powder blends?

The CGMPs require that all sampling plans be scientifically sound and representative of the
batch under test (see 21 CFR 211.160(b)). Further, in-process testing of powder blends to
demonstrate adequacy of mixing is a CGMP requirement (21 CFR 211.110). Between- and
within-location variability in the powder blend is a critical component of finished product
quality and therefore should be evaluated. Drug product manufacturers need to use a science-
and risk-based sampling approach to ensure (a) adequacy of blend mixing and (b) that
sampling of the blend is done at a suitable juncture in the manufacturing process. The
sampling and analysis needs to ensure that no differences exist between locations in a blend
that could adversely affect finished product quality. Traditional sampling using a powder-thief
may have drawbacks and limitations, such as causing disturbance to the powder bed, powder
segregation, or other sampling errors. However, powder-thief sampling remains widely used
and provides reliable results in many cases. The Agency encourages firms to adopt more
innovative approaches to ensuring adequacy of mixing (see, e.g., the guidance for industry PAT
—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality
Assurance). If a manufacturer proposes to use a thief sampling method, the reliability of the
method should be evaluated as part of analytical methods development.

References:
 FDA Guidance for Industry, 2004, PAT—A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance
19. For a nonsterile compendial drug product that includes an antimicrobial preservative in its
formulation, may I release and market lots of this drug product with initial out-of-specification
total aerobic plate counts if these lots test within specification 2 weeks later?

No. 21 CFR 211.113(a) requires appropriate written procedures to be established and followed
during manufacturing to prevent objectionable microorganisms in drug products not required
to be sterile.

Additionally, the second paragraph of USP General Chapter <51> Antimicrobial Effectiveness
Testing reads:

Antimicrobial preservatives should not be used as a substitute for good manufacturing

practices, solely to reduce the viable microbial population of a nonsterile product, or control
the presterilization bioburden of a multidose formulation during manufacturing.

Drug manufacturers should not rely on antimicrobial preservatives to reduce initial out-of-
specification plate counts to within-specification levels and then market the product. Section
211.165(f) mandates that drug products failing to meet established standards or specifications
be rejected. The initial test results exhibiting out-of specification levels of microbes are not
disqualified even if subsequent test results are within specifications. In such cases, FDA still
expects the manufacturer to reject the drug product based on the initial results.

It is also not acceptable for manufacturers to allow an inappropriately long time (e.g., weeks)
to pass before testing the product, which might permit the preservative to reduce levels of
microbes possibly introduced during manufacture and thus avoid out-of-specification test
results.
Finally, drug manufacturers should review their manufacturing process to determine
procedures or equipment that might introduce contaminating microorganisms into the process
or product.

References:
 21 CFR 211.113: Control of microbiological contamination
 21 CFR 211.165: Testing and release for distribution
 USP 38–National Formulary (NF) 33 (2015) General Chapter <51> Antimicrobial
Effectiveness Testing
 USP 38–NF 33 (2015) General Chapter <61> Microbiological Examination of Nonsterile
Products: Microbial Enumeration Tests
 USP 38–NF 33 (2015) General Chapter <62> Microbiological Examination of Nonsterile
Products: Tests for Specified Microorganisms