in process & bulk product

1. CGMP Regulations: Production System
21 CFR 211 Subpart F
Production and Process Controls
 Applies to Finished drug products
◈ Prescription drug products (Rx)
 NDA, ANDA, BLAs
◈ Over-The-Counter drug products (OTC)
◈ Unapproved drugs
◈ Compounded drugs (under Sec. 503B of the Act)
◈ Any type of Method of Manufacture
 Batch, Semi-continuous, Continuous
 Aseptic, Sterile, Biotechnology
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2. Production System
 Production System includes
◈ measures and activities to control the manufacture of
in-process materials and drug products including
 batch compounding
 dosage form production
 in-process sampling and testing and
 process validation
◈ establishing, following, and documenting
performance of approved manufacturing procedures
 See 21 CFR 211 Subparts B, F, I, and J
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3. Typical Pharmaceutical
Manufacturing Operations
Blending
Dosage FormFormation
Compression, Filling
Coating, polishing
Packaging
Dispensing
Mixing
Filtration*
CCS Filling**
Packaging
Dispensing
Mixing
Device Filling
Device Assembly
Packaging
Dispensing
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Liquids/Suspensions
Solid Orals:
Tablets, caplets
Drug-Device
Nasal Sprays, MDI. DPI

4. 21 CFR211 Subpart F
Production and ProcessControls
§ 211.100 - Written procedures; deviations
§ 211.101 - Charge-in of components
§ 211.103 - Calculation of yield
§ 211.105 - Equipment identification
§ 211.110 - Sampling and testing of in-process materials and drug products
§ 211.111 - Time limitations on production.
§ 211.113 - Control of microbiological contamination
§ 211.115 - Reprocessing
Subpart I - Laboratory Controls: § 211.160(b)(2)(3) - Sampling procedures for
in-process materials and finished drug products
Subpart J - Records and Reports: § 211.180(e)(2)(3) - Annual Product Review
§ 211.192 – Production Record Review, Deviation and investigation
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5. § 21 CFR211.100
Written procedures; deviations – Key points
(a) Requires written procedures for production and process control
◈ designed to assure that the drug products have the identity,
strength, quality, and purity they purport or represent to possess.
◈ shall include all requirements in this Subpart F
◈ Responsibility of the appropriate organizational units to
draft the procedures including any changes, review, and approve
◈ Responsibility of the quality control unit to review and approve
(b) The written PPC procedures shall be
◈ followed in the execution of the various production and process
control (PPC) functions
◈ documented at the time of performance
◈ any deviation from the written procedures shall be recorded and
justified
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6. § 21 CFR 211.101
Charge-in of components –
Key points
Written PPC procedures shall include the following:
(a)The batch shall be formulated with the intent to provide not less
than 100 percent of the labeled or established amount of active
ingredient
(b)Components for drug product manufacturing shall be weighed,
measured, or subdivided as appropriate.
◈ If a component is removed from the original container to another,
the new container shall be identified with the following information:
(1) Component name or item code;
(2) Receiving or control number;
(3) Weight or measure in new container;
(4) Batch for which component was dispensed, including its product
name, strength, and lot number.
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7. § 21 CFR 211.101
Charge-in of Components –
Key points
Written PPC procedures shall include the following:
(c) Weighing, measuring, or subdividing & dispensing of components
Manual operation:
 Requires adequate supervision by a second
 Second person must examine and assure
(1) release of the components to Mfg. by the quality control unit (QCU)
(2) the weight/measure matches the Batch Production Records (BPRs)
(3) proper identification of the containers
Automated equipment Operation (211.68):
 Requires only one person to verify theses operations and assure (c)(1)-(3)
(d) Component addition: (e.g., order of addition)
 Manual Operation: Require one person to add and a second to verify
 Automated equipment Addition(211.68): Require one person to verify
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8. § 21 CFR 211.103
Calculation of yield – Key
points
 Requires determination of actual yields and %
theoretical yield
◈ at the conclusion of each appropriate phase of manufacturing,
processing, packaging, or holding of the drug product.
 Yield calculations
◈ performed by one person
◈ independently verified by a second person
 Yield calculations by automated equipment (211.68)
◈ independently verified by one person
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9. 21 CFR 211.105
Equipment identification – Key
points
(a) Requires proper identification (ID) of all equipment at all times
during production
◈ compounding and storage containers
◈ processing lines
◈ major equipment
 to indicate their contents
 to indicate the phase of processing of the batch when necessary
(b) Requires identification and recording of a major equipment by a
distinctive ID number or code in the batch production record
◈ to show the use of a specific equipment for manufacture of each DP batch
◈ ID by equipment name allowed in lieu of a distinctive ID number or code
 if only one of a particular type of equipment exists in a facility
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10. § 21 CFR 211.110 - Sampling & testing of
in-process materials & drug products – Key points
(a) Requires establishing and following written procedures
 To assure batch uniformity and integrity of drug
products
 That describe the in-process controls, and tests, or
examinations to be conducted on
◈ appropriate samples of in-process materials of each batch
 To monitor the output and validate the performance
of those manufacturing processes
◈ responsible for causing variability in the characteristics of
in-process material and the drug product
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11. § 21 CFR 211.110 - Sampling & testing of
in-process materials & drug products - Key points
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(a) Requires establishing and following written procedures
 Such control procedures shall include, but are not
limited to, the following (characteristics), where
appropriate:
(1) Tablet or capsule weight variation
(2) Disintegration time
(3) Adequacy of mixing to assure uniformity and
homogeneity
(4) Dissolution time and rate
(5) Clarity, completeness, or pH of solutions
(6) Bioburden testing

12. § 21 CFR 211.110 - Sampling & testing of
in-process materials & drug products - Key points
(b) Requires establishing valid in-process specifications for
such characteristics
◈ shall be consistent with drug product final specifications
◈ shall be derived from previous acceptable process
average and process variability estimates where possible
◈ determined by the application of suitable statistical
procedures where appropriate.
◈ Examination and testing of samples shall assure that the
drug product and in-process material conform to
specifications.
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13. § 21 CFR 211.110 - Sampling & testing of
in-process materials & drug products - Key points
(c) Requires testing of in-process materials for identity,
strength, quality, and purity as appropriate
Requires the quality control unit to approve or reject the
in-process materials during the production process, e.g.,
 at commencement or completion of significant phases
 or after storage for long periods
(d) Requires identification and control of the rejected in-
process materials under a quarantine system
 designed to prevent their use in manufacturing or
processing operations for which they are unsuitable
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14. § 21 CFR 211.111
Time limitations on production- Key points
 Requires to establish time limits for the completion of
each phase of production when appropriate
◈ to assure the quality of the drug product.
 Any deviation from established time limits may be
acceptable
◈ if such deviation does not compromise the quality of the drug
product.
 Such deviation shall be justified and documented.
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15. § 21 CFR 211.113
Control of microbiological contamination
(a) Appropriate written procedures,
designed to prevent objectionable
microorganisms in drug products
not required to be sterile, shall be
established and followed.
(b) Appropriate written procedures, designed to prevent
microbiological contamination of drug products
purporting to be sterile, shall be established and
followed. Such procedures shall include validation of all
aseptic and sterilization processes.
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16. § 21 CFR 211.115
Reprocessing - Key Points
(a) Requires establishing and following procedures
 Prescribing a system for reprocessing batches that
do not conform to standards or specifications
 Steps to insure that the reprocessed batches will
conform with all established standards,
specifications, and characteristics
(b) Reprocessing shall not be performed without the
review and approval of the quality control unit.
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17. Sec. 21 CFR 211.160 (b)
General requirements - Key Points
In-process Materials:
(2) Requires determination of conformance to
◈ written specifications and sampling and testing
procedures
◈ samples shall be representative and properly identified
Drug Products:
(3) Requires determination of conformance to
◈ written descriptions of sampling procedures and
appropriate specifications for drug products.
◈ samples shall be representative and properly identified
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18. Sec. 21 CFR211.180 (e)
General requirements – Key
Points
(e) Requires maintaining and evaluating written records and data at
least annually
 to evaluate the quality standards of each drug product
 to determine the need for changes in drug product
specifications or manufacturing or control procedures
Requires establishing and following procedures for such
evaluations and include provisions for:
(1) A review of a representative number of batches, whether
approved or rejected, and, where applicable, records
associated with the batch.
(2) A review of complaints, recalls, returned or salvaged drug
products, and investigations conducted under 211.192 for
each drug product
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19. Sec. 21 CFR211.192
Production Record Review- Key
Points
 Requires thorough investigation of any unexplained
discrepancy whether or not the batch has already been
distributed
◈ exceeding the maximum or minimum of a theoretical yield
established in master production and control records
◈ failure of a batch or any of its components to meet any of its
specifications
 Requires to extend investigation to other batches
◈ same drug product and other drug products that may have been
associated with the specific failure or discrepancy
 Requires a written record of the investigation with
conclusions and follow-up
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