THE WHOLE ACTIVE PHARMACEUTICAL INGREDIENT STORY

Gary L. Gray
GGray Consulting, LLC
1236 S. Geyer Rd.
Kirkwood, MO 63122
314-822-7210
ggrayconsults@earthlink.net

SUMMARY

This write-up is a summary of the oral presentation. The purpose of the actual presentation was to give general
information on the control of Active Pharmaceutical Ingredient manufacturing processes and specifically on the application
of Food and Drug Administration Guidance, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients. A significant amount of time was intentionally left for questions. The secondary title for the presentation is
“what you always wanted to know about Active Pharmaceutical Ingredients but were too busy to ask”. For those who did not
attend the presentation or were not able to ask their questions, please contact me at the above email address. I will be happy
to try to answer any questions.

INTRODUCTION

An Active Pharmaceutical Ingredient (API) is any substance or mixture of substances that is used in the
manufacture of a dosage form drug product and that is intended to furnish pharmacological activity or other direct effect in
the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
APIs have been around as long as people have made and used drugs. However, they have not always been called
Active Pharmaceutical Ingredients. In the 1960’s and 1970’s they were called Fine Chemicals or Drug Substances. In the
1980’s and 1990’s they were Bulk Pharmaceutical Chemicals (BPC). The term API did not come into general use until just
the last several years.

PROCESSES FOR APIS VS DOSAGE FORM DRUGS

Control of the manufacturing processes for APIs is just as important as control of the manufacturing processes for
dosage form drugs. The purity, safety and effectiveness of a dosage form drug cannot be assured unless the manufacture of
any APIs used was properly controlled. However, the processes for manufacture of APIs and dosage form drugs are very
different and therefore the systems for controlling the processes must be different.
Starting materials for APIs and dosage form drugs are different. APIs are produced from starting materials such as:
basic industrial chemicals that may be organic, inorganic, hazardous or even toxic; botanical materials; or mined minerals.
Starting materials for dosage form drugs are APIs and excipients; both FDA regulated products
The manufacturing processes for APIs typically include process steps such as chemical or biological reactions,
crystallizations, distillations, filtrations, extractions and separations. In a typical API process the starting material are
changed at the molecular level and refined into the finished API. Only small amounts of the starting materials actually
remain in the API. Manufacturing processes for dosage form drugs on the other hand typically include process steps such as
mixing, blending, granulating, dissolving, compressing, or coating. In general all the materials that enter the process for a
dosage drug remain in the final product.
The facilities for producing APIs can also be different than the facilities where dosage form drugs are produced.
API facilities are typical of those processing any chemical product. They are often of open bay construction, not well
enclosed or even outdoors. Closed equipment is the basis for maintaining product isolation. Only final packaging areas and
other places where product is handled in the open are well contained. On the other hand dosage form drug products are
typically produced in tightly constructed buildings with sophisticated air handling systems because operation routinely
include handling materials and products in the open.

HISTORY OF GMPS FOR APIS

In the 1960’s the Food and Drug Administration (FDA) set the standard for controlling the manufacturing processes
for dosage form drug products, i.e. 21CFR211. A standard for control of the manufacturing process for an API was not
published by FDA until August 2001.
 In 1963 the FDA promulgated the first regulation on Good Manufacturing Practice for dosage form drugs:
21CFR211, Current Good Manufacturing Practice for Finished Pharmaceuticals. The FDA began to be more interested in
regulating and inspecting bulk drug manufacturers in the late 1960s and early 1970s. It was soon apparent that 21CFR211
could not be fully and satisfactorily applied to API manufacturing. FDA considered a separate regulation for GMPs for bulk
drugs and in fact, did initially state that 21CFR212 would be developed as a GMP for bulk drugs. However, this was never
done.
In 1984 FDA first published a guide for their inspectors, Guide to Inspection of Bulk Pharmaceutical Chemicals,
which recognized the differences between processes for manufacturing APIs and finished pharmaceuticals. This guide did not
give a full description of GMPs for bulk drugs but rather noted where deviations from strict compliance with 21CFR211
should be expected and were acceptable. The many areas where bulk drug processes were different from finished
pharmaceutical processes were noted and how compliance with GMPs should be assessed in these areas was described. The
guide was, of course, also available to API manufacturers and was used to direct their efforts toward compliance with GMPs.
The International Conference on Harmonization (ICH) was established in 1990 by the European Union (EU), Japan
and the United States (US). Its purpose was to reduce duplication of effort during research and development of new drugs
while safeguarding quality, safety and efficacy. In 1998 the ICH formed an Expert Working Group, with members from
regulatory agencies and manufacturers associations in the three regions, which was assigned to develop a common standard
for Good Manufacturing Practice in the manufacture of active ingredients for dosage form drug products. The topic was
designated as Q7A with Q for the quality area, 7 for the seventh topic in this area and A for first sub-topic. This Expert
Working Group adopted the term Active Pharmaceutical Ingredient for drug substance, active ingredient, bulk drug, etc.
After many meetings and a draft that was published for comment in 2000, the final version was approved by the regulatory
members from the three regions in November 2000 and recommended for adoption by the regulatory agencies in each region.
In August 2001 the FDA adapted the final draft to their guidance format and published Q7A Good Manufacturing Practice
Guidance for Active Pharmaceutical Ingredients (Q7A).
This guidance is now the definitive standard for GMP in the manufacture of APIs.

GMP GUIDANCE FOR APIS (Q7A)

Q7A was published as a guidance rather than a regulation by FDA. I believe this was done to speed the publication
process since approval by congress and comments from industry are not necessary for a guidance. The Food Drug and
Cosmetic Act gives FDA authority to regulate both dosage form drugs and APIs and requires that both are manufactured in
conformance with current GMPs. Guidance Q7A is the way FDA has chosen to communicate their requirements for GMP in
API manufacture. A manufacturer in full compliance with Q7A will satisfy the requirement.
Q7A describes a complete quality management system requiring a documented system, active participation by
management, defined responsibilities and authorities, an independent quality unit (QU), written procedures and processes,
investigation of deviations, and release of final APIs by the QU. The guidance includes nineteen sections that cover the
details of the quality system. I will briefly review the contents of each section.
Section I defines the purpose, scope and applicability. Section II covers the general principles listed above, defines
specific responsibilities of the QU and production unit, requires internal audits to assure continuing compliance, and requires
regular product reviews to assure consistency over time.
Section III, PERSONEL, requires that there be an adequate number of people qualified by education, training and
experience to carry out and supervise the work done. Protective clothing and personal hygiene are required to protect the API
from contamination. Regular training in the jobs performed and how GMPs apply to those jobs is required. Any consultants
used should be qualified by education, experience and training to give advice on the subject for which they are used. The
requirements of this section are similar to those of 21CFR211.
Section IV, BUILDINGS and FACILITIES, requires that buildings and facilities be located, designed and
constructed as is appropriate for the type and stage of processing being executed. There should be adequate space for and an
orderly arrangement of manufacturing operations. Equipment can be outdoors when there is adequate protection from
contamination. Minimizing the risk of contamination and cross-contamination is very important. Utility systems should be
qualified. Water used in the processing of an API should be suitable for the intended use and at least equivalent to potable
water. Laboratory operations should normally be in a separate area. Buildings should be properly maintained and kept clean.
Section V, PROCESS EQUIPMENT, requires that equipment be of adequate size and design for its intended use.
Food grade oils and lubricants should be used when possible. Prevention of contamination and cross-contamination again is
very important. There should be written procedures for preventive maintenance and cleaning. Dedicated equipment should
be cleaned at appropriate intervals to prevent carryover of contaminates. Non-dedicated equipment should be adequately
cleaned between production runs of different products to prevent cross-contamination. Control equipment for critical
parameters should be calibrated according to written procedures and established schedules. Quality related computerized
systems should be appropriately qualified or validated based on the complexity and criticality of the application.
Unauthorized access to computerized systems should be appropriately controlled. A back-up system should be provided if
failure of a system would result in permanent loss of records.
Section VI, DOCUMENTATION and RECORDS, requires a document control system that specifies how
documents and procedures will be prepared, reviewed, approved, distributed, revised and controlled. Specifications should
be established for all raw materials, intermediates, APIs and labeling and packaging materials. Records showing receipt,
supplier, quantity, lot number, testing or examination, approval or rejection, and tracing use of these materials should be
maintained. Records showing use, maintenance and cleaning of major equipment should be maintained. Master production
instructions should be prepared and approved by the QU. A production record should be completed for each batch that
documents date of production, materials used, in-process testing, yields, any deviations and results of release testing.
Records of laboratory testing should be prepared and retained including all raw data and calculations. Written procedures
should be established requiring review and approval of all batch production and laboratory control records before each batch
is released. Only batch production and laboratory control records of critical process steps must be reviewed by the QU.
Except for permitting the review of non-critical records by other than the QU, the requirements of this section are similar to
those of 21CFR211.
Section VII, MATERIALS MANAGEMENT, requires that written procedures be established for the receipt,
identification, sampling, testing, approval or rejection, and storage of materials. Materials should be held in quarantine until
approved for use. Material may be approved for use based on an identification test and review of an accompanying
Certificate of Analysis (CofA) provided that the supplier has been appropriately evaluated. Receipt of materials in bulk
containers and commingling of new materials with existing stocks in silos is expected. Materials in suitable container may be
stored outdoors.
Section VIII, PRODUCTION and IN-PROCESS CONTROLS, requires that raw materials charged to the process be
weighed or measured using suitably accurate devices. Critical weighing or measuring should be witnessed or subject to
equivalent control. Actual yields should be compared to expected values. Any deviations should be documented and
explained. Critical deviations should be investigated. Written procedures should be established to monitor and control the
process including any in-process testing. In-process tests can be performed by production personnel and adjustments made to
the process without QU approval within established limits that have been approved by the QU. Blending materials that are
within the same specification is acceptable. Out-of-specification (OOS) batches should not be blended with other batches for
the purpose of meeting specification. Carryover of materials from one batch to the next is expected in reactors, crystallizers,
centrifuges, mills, etc. This is acceptable as long as product quality is not adversely affected.
Section IX, PACKAGING and LABELING, requires written procedures for the receipt, quarantine, testing or
examination, release and handling of packaging and labeling materials and for packaging and labeling operations. Containers
should adequately protect the API from deterioration and contamination. Containers may be reused as long as they are
cleaned and inspected under documented procedures. Label control and reconciliation is required. Packaging and labeling
operations should be controlled to prevent errors and mix-ups. Tamper evident seals are required. Except for permitting
reuse of containers, the requirements of this section are similar to those of 21CFR211.
Section X, STORAGE and DISTRIBUTION, requires that proper facilities be available for the storage of materials
and APIS under appropriate conditions. When materials are stored, either physical separation or other equivalent means
should be used to prevent unauthorized use of quarantined, rejected, returned, or recalled materials. APIs should only be
distributed to third parties after they have been released by the QU. Complete distribution records must be kept to permit
recall of an API, if necessary. The requirements of this section are similar to those of 21CFR211.
Section XI, LABORATORY CONTROLS, requires that the independent QU have adequate laboratory facilities at
its disposal. Documented procedures should describe sampling, testing, and approval or rejection of materials, as well as
recording and retention of data. Each batch of an API should be tested to determine conformance to specification. A CofA
should be issued for each batch of API on request. A documented, on-going testing program should be established to monitor
the stability of the API. An impurity profile should be established for the API. Reserve samples should be retained for each
batch of the API to permit future evaluation. The requirements of this section are similar to those of 21CFR211.
Section XII, VALIDATION, requires a document statement of the company’s policy and approach to validation of
production processes, cleaning procedures, analytical methods, and computerized control systems. Prospective, retrospective
and concurrent validations are defined and the appropriate application of each is discussed. Written protocols and reports are
required. Critical equipment should be appropriately qualified. Cleaning procedures should normally be validated.
Analytical methods that are not included in a relevant pharmacopoeia or other standard reference should be validated.
Section XIII, CHANGE CONTROL, requires that a formal change control system be established to evaluate all
changes that could affect the quality of the API. All changes must be appropriately evaluated both before and after
implementation. Any change implemented must be approved by the QU. Customers manufacturing dosage form drug
products should be notified of any change that could affect the quality of the API.
Section XIV, REJECTION and RE-USE of MATERIALS, recognizes that APIs failing to meet specification may be
reprocessed or reworked. Reprocessing is introduction of an API back into a process to repeat steps of the established
process. Reworking is subjecting an API that does not meet specifications to one or more processing steps that are not part of
the established process. Rework processes should be validated, often by concurrent validation. Recovery and reuse of
unreacted materials, mother liquors and solvents is acceptable provided they meet suitable specifications. Recovered
solvents can be reused in the same or different processes and commingled with fresh solvent provided they meet suitable
specifications. Returned materials should be quarantined. They may be reprocessed, reworked or destroyed as is appropriate.
Section XV, COMPLAINTS and RECALLS, requires that all quality related complaints be recorded and
investigated according to a written procedure. Records of complaints should be retained and reviewed to evaluate trends and
the need for additional corrective actions. A written procedure should define the circumstances under which a recall of an
API would be considered and covering all aspects of any recall that is initiated. The requirements of this section are similar
to those of 21CFR211.
Section XVI, CONTRACT MANUFACTERS, and Section XVII, AGENTS, BROKERS, DISTRIBUTORS, ETC.,
are not stand alone sections. Instead they describe how the previous fifteen sections apply to these areas and how
relationships with the API manufacturer should be handled. Review of these sections will not be part of the presentation.
Section XVIII, APIs from CELL CULTURES, and Section XVIX, APIs for CLINICAL TRIALS, are also not stand
alone sections. Additional and reduced requirements for these types of API production are discussed. Review of these
sections will not be part of the presentation.

CONCLUSION

FDA’s guidance Q7A is the current definitive standard for GMP in the manufacture of any API. All API
manufacturers should be using this guide as a basis for their compliance activities.

GUESTIONS AND ANSWERS

As stated in the summary the secondary title of this presentation is “what you always wanted to know about Active
Pharmaceutical Ingredients but were too busy to ask”. Approximately forty percent of the time allotted is to be used to
answer questions the audience will have on API manufacturing in general and on the application of Q7A to control API
manufacturing processes.

REFERENCES

- FDA Guidance for Industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
www.fda.gov/cder/guidance/4286fnl.htm

- Code of Federal Regulation, 21CFR211