Journal of GXP Volume 6 Number 4 July Institute of Validation

Compliance 2002 Tecnology

Conference Report
A Practical Approach to the International Conference on Harmonization Q7A GMP Guidance
for Active Pharmaceutical Ingredients
by
John W. Waggener
Contributing Editor, Institute of Validation Technology
The future is now for manufacturers of Active Pharmaceutical Ingredients (APIs) with the
publication of the Q7A Guidance for Good Manufacturing Practice. San Juan, Puerto Rico was the
site for a comprehensive workshop, sponsored by the Parental Drug Association (PDA), Generic
Pharmaceutical Association (GphA), Pharmaceutical Research and Manufacturing Association
(PhRMA), and the U.S. Food and Drug Administration (FDA). This workshop had two main goals: to
introduce the basic concepts of the Q7A guidance, and to offer a glimpse of the rationale and intent
of the designers of the document as it applies to API. Each section of Q7A was presented by a
member of the Expert Working Group (EWG) who, under the umbrella of the International
Conference on Harmonization (ICH), forged the guidance in an effort to bring direction and
consistency to API manufacturing.
The Q7A guidance is a historical document because it represents the first internationally
harmonized tripartite GMP guidance developed jointly by industry and regulators under ICH
direction. It establishes one global GMP standard for API, and intends to provide mutual recognition
of GMPs in API production. It impacts any manufacturer, worldwide, that markets API throughout
those countries that are members of the World Health Organization (WHO), including those that use
API in non-prescription drug products.

This article presents a practical overview of the principles found in the guidance by providing a
general discussion of its origin, citing specific expectations, and by drawing a distinction between
the recommendations specific to API and those associated with finished dosage forms of
pharmaceutical products. This distinction is very important. The assumption is made throughout
much of the industry that API production falls under the same regulatory requirements as finished
dosage forms for cGMP, specifically 21 Code of Federal Regulations (CFR) Parts 210 and 211. This is
not true, however, many of the expectations in Q7A follow the same logical approach to GMP as 21
CFR 210 and Part 211. Specifically, in the preamble of 21 CFR 211, in the commissioner’s
comments, it states that the requirements of the CFR do not apply to API.

This tends to be a point of confusion and controversy. Many API manufacturers still maintain that
regulatory agencies hold them to the GMP standards cited in the CFR’s regardless of the
commissioner’s comments. The regulatory expectations are discussed in the following sections, but
it is fair to say that there was a dire need for the development of the Q7A guidance, because many
of the stipulations in CFR 210 and 211 cannot be appropriately applied to API manufacturing. The
fact that many of the sound GMP principles found in the CFRs are echoed in Q7A, speaks to the
universality of the concepts, but does not imply that the CFRs are the regulatory requirement to
which API manufacturers are bound. During the discussion of the specific sections of Q7A, this
article will describe the general expectations of the guidance and illustrate the similarity (or
differences) between Q7A recommendations and the requirements in CFR 210 and 211. While Q7A
is not a regulation, FDA has its enforcement authority for APIs from the Food, Drug and Cosmetic
(FD&C) Act (Section 510(a)(2)(B) itself.

The many differences between API manufacturing and finished dosage form pharmaceuticals
required an objective evaluation of what constitutes a state of control, while allowing API
manufacturers the flexibility to operate under a vast array of situations and production
environments. To complicate matters further, Q7A has an international audience. The ICH was
formed to standardize the expectations for drug manufacture in the countries governed by the
WHO. Q7A is just one of a series of guidances developed by the ICH to harmonize regulatory
approaches used in the United States, Europe, and Japan. All of the “Q Series” guidances are
focused on quality. The authors of Q7A are the members of the EWG, which consists of qualified
industry and regulatory professionals. Its charter was to design a guidance for API manufacturing
that would promote international standards of GMP, while allowing for the flexibility required to
support the inherent diversity throughout all API production environments. Some variability
throughout API manufacturing is subtle, but significant. Even terminology and definitions had to be
addressed. Until recently, API products were, and still are, referred to as “bulk” pharmaceuticals.
This generic term applies to both API and excipients. Q7A strives to define these terms and focuses
on the active material. This is a difficult concept because how we define an API starting material,
dictates what is considered an “intermediate” or “active” compound, and just how and where the
Q7A API GMP applies. Q7A uses API and “drug substance” terms synonymously.

The goal of this article is not to restate the Q7A guidance, but reviewing certain basic concepts is
important to understanding the intent of Q7A and its approach to GMP. Q7A defines some of these
critical terms:

Active Pharmaceutical Ingredients Starting Material

API starting material should be considered to have the following characteristics. This applies to
chemical synthesis only.

• A material used in the production of an API that is incorporated as a significant structural

fragment into the structure of the API.
• May be an article of commerce, a material purchased from one or more suppliers under
contract or commercial agreement, or may be produced in-house.
• Starting materials are normally composed of defined chemical properties and structure.

Intermediate

A material produced during API processing that undergoes further molecular change or purification
before it becomes the API. It may or may not be isolated.

The intended use clause states that:

Any substance or mixture of substances intended to be used in the manufacture of a drug

(medicinal) product and that, when used in the production of a drug, becomes an active ingredient
of the drug product.

The pharmacological activity clause:

Such substances are 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.

The history and intent of Q7A is obvious; to provide API manufacturers with a baseline standard of
operation that is consistent throughout the world, and comply with the intent and purpose of GMP.
Audit philosophy must take in consideration the differences between API and dosage form products,
as the Q7A guidance does. From a regulatory perspective, adherence to Q7A is synonymous with
operating in a state of control per any international GMP expectation.

General Application of Q7A

As stated before, the FDA CFRs do not specifically apply to API, and the Q7A guidance has been
established to provide direction on a global scale. It is important to remember, however, that Q7A
is a guidance and not a statutory regulation. Nonetheless, the global community has accepted Q7A
as the definitive standard for API manufacturing. The WHO has recommended that Q7A replace its
current GMP for API because it more comprehensive and scientifically sound. Q7A has been adopted
by the Pharmaceutical Inspection Cooperation Scheme (PIC/S) to replace its guidelines for API. In
addition, to being adopted by Australia’s Therapeutic Goods Administration (TGA), Q7A has been
published as Annex 18 to the European Union (EU) Guide to Good Manufacturing Practice. In March,
1998, the FDA produced the Draft Guidance for Industry – Manufacturing, Processing, or Holding
Active Pharmaceutical Ingredients. This has been replaced with Q7A. In addition, the Agency plans
to revise the 1991 Guide to Inspection of Bulk Pharmaceutical Chemicals to comply with the
standards set in Q7A. So regulation or not, Q7A is the standard to which API manufacturers will be
held responsible to establish and maintain their GMP operations.

To this end, it is important to understand the scope of Q7A. It applies to APIs manufactured for use
in human drug (medicinal) products, including sterile APIs, but only up to the point immediately
before the API is rendered sterile. This includes APIs manufactured by chemical synthesis,
extraction, cell culture/fermentation, recovery from natural sources, or any combination of these
processes. In addition, Q7A applies to APIs used in the production of drug products for clinical
trials, and APIs produced using blood or plasma as Raw Materials (RMs). It includes APIs or
intermediates manufactured by cell culture or fermentation using natural or recombinant
organisms.

Q7A applies to a specific set of activities that define the manufacturing process:

• Receipt of materials
• Production
• Packaging and repacking
• Labeling and relabeling
• Quality control and release
• Storage and distribution

A key concept to understand is that Q7A is designed to be more flexible than FDA regulations to
accommodate the diversity of API production environments. Each firm is responsible for
documenting the rationale of any deviations in areas where flexibility is allowed, but Q7A is quite
explicit in some areas.

There are significant exclusions as well. Q7A does not apply to all vaccines, whole cells, whole blood
and plasma, blood derivatives (plasma fractionation), and gene therapy APIs. Neither does it apply
to medical gases, bulk packaged drug (medicinal) products, or radiopharmaceuticals. Q7A does not
address APIs intended for veterinary drug products, however, it is recommended that the standards
be adhered to nonetheless. This guidance does not apply to registration and filing requirements for
APIs within the context of marketing/manufacturing authorizations or drug applications.
Given the diversity of API manufacturing, and considering that Q7A is a guideline, each API
manufacturer is responsible for interpretation and application of Q7A as they feel appropriate. This
is where the differences between API manufacturing and dosage form pharmaceuticals become
significant. This article discusses some of the specific differences between the two, but consider, for
now, how difficult (if not impossible) it would be for an API manufacturer whose entire operation is
outside a contained building to comply with some aspects of CFR Parts 210 and 211. Pest control
alone constitutes a major discrepancy. The same GMP concepts are valid in dosage form and API
manufacturing, but the application of these concepts may differ.
If the product has no opportunity, for example, for exposure to the outside environment, pest
control outside of a contained building is not necessary. This does not compromise the expectation
that pests represent a significant challenge to the integrity of the product, however under the
circumstances, is does not apply.
Determining the level of compliance recommended by Q7A is quite straightforward. A firm needs to
evaluate the impact of Q7A on their working environment.
• If Q7A says that you should do something, you probably should do it.
• If Q7A doesn’t say you have to do something, you probably don’t have to.
• If Q7A doesn’t prohibit something, it’s probably acceptable.
• If Q7A prohibits something, you probably shouldn’t do it.